Pyridazinone compounds

[0001] The present invention relates to pyridazinone compounds.

Background of the invention [0002] Phosphodiesterases (PDEs) are a superfamily of enzymes encoded by 21 genes and divided into 11 different families according to structural and functional properties. These enzymes inactivate the ubiquitous intracellular secondary messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); PDEs selectively catalyze the hydrolysis of 3'-ester bonds, forming inactive 5'-monophosphate. Based on the substrate specificity, the PDE families can be further classified into 3 groups i) cAMP-PDE (PDE4, PDE7, PDE8), ii) cGMP-PDE (PDE5, PDE6 and PDE9) and iii) Double substrate PDE (PDE1, PDE2, PDE3, PDE10 and PDE11).

[0003] cAMP and cGMP are involved in the regulation of virtually every physiological process, such as the production and operation of proinflammatory mediators, ion channel activity, muscle relaxation, learning and memory, differentiation, apoptosis, lipogenesis, glycogenolysis and gluconeogenesis. In particular, in neurons, these secondary messengers play an important role in regulating synaptic transmission as well as in the differentiation and survival of neurons (Nat. Rev. Drug Discov. 2006, vol. 5: 660-670). The regulation of these processes using cAMP and cGMP is accompanied by the activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate various substrates, including transcription factors, ion channels and receptors that regulate various physiological processes. Intracellular cAMP and cGMP concentrations appear to be temporarily, spatially and functionally divided by regulation of adenyl cyclase and guanyl cyclase in response to extracellular signals and their degradation by PDE (Circ. Res. 2007, vol. 100 (7): 950-966) . PDEs provide the only way to degrade cyclic cAMP and cGMP nucleotides in cells, so PDEs play a critical role in cyclic nucleotide signaling. In this regard, PDE could be a promising target for various therapeutic drugs.

[0004] Phosphodiesterase 10A (PDE10A) was discovered in 1999 by three independent groups (Proc. Natl. Acad. Sci. USA 1999, vol. 96: 8991-8996, J. Biol. Chem. 1999, vol. 274: 18438- 18445, Gene 1999, vol. 234: 109-117). Expression studies have shown that PDE10A has the most limited distribution among all known PDE families; PDE10A mRNA is highly expressed only in the brain and testes (Eur. J. Biochem. 1999, vol. 266: 1118-1127, J. Biol. Chem. 1999, vol. 274: 18438-18445). In the brain, mRNA and the PDE10A protein are very 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: MSN, which express the D1 dopamine receptors responsible for the direct pathway (nigrostriatal) and MSNs, which express the D2 dopamine receptors responsible for the direct pathway (striatal band - pale knob). The function of the direct pathway is planning and execution, while the function of the direct pathway is to act as a brake on behavioral activation. Because PDE10A is expressed in both types of MSN, PDE10A inhibitors could activate both of these pathways. The antipsychotic efficacy of current drugs, D2 or D2 / 5-HT2A antagonists, is mainly due to their activation of the indirect pathway in the striatum. Because PDE10A inhibitors are capable of activating this pathway, this suggests that PDE10A inhibitors are promising as antipsychotic drugs. Excessive antagonism of D2 receptors in the brain by D2 antagonists causes problems with extrapyramidal side effects and hyperprolactinemia. However, PDE10A expression is limited to these striatal pathways in the brain, and therefore side effects caused by PDE10A inhibitors are expected to be weaker compared to current D2 antagonists. Regarding hyperprolactinemia, PDE10A inhibitors would not increase prolactin levels due to the lack of D2 receptor antagonism in the pituitary gland. In addition, the presence of PDE10A in the direct pathway makes it likely that PDE10A inhibition has some advantages over current D2 antagonists; it is believed that the direct pathway promotes the desired effect and activation of this pathway with PDE10A inhibitors may counter extrapyramidal symptoms caused by excessive antagonism of D2 receptors. In addition, activation of this pathway could facilitate striatal-thalamic impulse, favoring the implementation of procedural strategies. In addition, increasing levels of secondary messengers without blocking dopamine receptors and / or other neurotransmitter receptors may also provide therapeutic benefits with less adverse side effects compared to current antipsychotic drugs (e.g. hyperprolactinemia and weight gain). This unique distribution and function in the brain indicates that PDE10A is an important new target for the treatment of neurological and psychiatric disorders, in particular psychotic disorders such as schizophrenia.

[0005] As a phosphodiesterase (PDE) 10 inhibitor, pamphlet WO2006 / 072828 discloses a compound represented by the formula:

<img file="PL2393360T3_D0001.tif" />

^k; HET¹1 wherein Z is [0006] Furthermore, as a phosphodiesterase (PDE) 10 inhibitor, pamphlet WO2008 / 001182 also discloses a compound represented by the general formula

<img file="PL2393360T3_D0002.tif" />

[0007] Additionally, US 2008/207902 discloses pyrazolopyridin-4-yl-pyridazinone derivatives as phosphodiesterase inhibitors.

Summary of the Invention

Technical problem [0008] However, the development of new phosphodiesterase (PDE) 10A inhibitors is still required.

Solution to the problem [0009] The inventors of the present invention have found that the compound represented by the formula (Io) or a salt thereof (referred to herein as the compound (Io)) exhibits PDE 10A inhibitory activity and after extensive research completed the present invention.

[0010] Among the compounds (Io), the compound represented by the formula (I) or a salt thereof (referred to herein as compound (I)) is a new compound.

[0011] In the present specification, the compound (Io) comprising the compound (I) is also referred to as the compound of the present invention.

[0012] That is, the present invention provides the following solutions.

[1] Compound of formula (I)

<img file="PL2393360T3_D0003.tif" />

wherein

R¹ is a substituent

R² is a substituent, o

R³ is a hydrogen atom or a substituent, ring A is an aromatic ring which may be substituted, and ring B is a 5-membered heteroaromatic ring which may be substituted;

3 wherein the substituent for R¹, R² or R³, the "aromatic ring which may be substituted" for ring A or the substituents of the "5-membered heteroaromatic ring which may be substituted" for ring B are selected from the group A of substituents;

[Group A substituents] [0013] (1) a halogen atom;

(2) nitro group;

(3) cyano group;

(4) a carboxy group that can be esterified;

(5) C1-10 alkyl which may be substituted;

(6) a C2-6 alkenyl group which may be substituted;

(7) a C2-6 alkynyl group which may be substituted;

(8) a C3-7 cycloalkyl group which may be substituted;

(9) C6-14 aryl which may be substituted;

(10) a C7-16 aralkyl group which may be substituted;

(11) C6-14 aryl-C2-6 alkenyl which may be substituted;

(12) heterocyclic group which may be substituted;

(13) hydroxyl group;

(14) a C1-10 alkoxy group which may be substituted;

(15) a C3-7 cycloalkyloxy group which may be substituted;

(16) C6-14 aryloxy which may be substituted;

(17) a C7-16 aralkyloxy group which may be substituted;

(18) a C1-10 alkylcarbonyloxy group which may be substituted;

(19) a C1-10 alkoxycarbonyloxy group which may be substituted;

(20) mono-C 1-10 alkylcarbamoyloxy which may be substituted;

(21) a di-C1-10 alkylcarbamoyloxy group which may be substituted;

(22) C6-14 arylcarbonyloxy group which may be substituted;

(23) mono- or di-C6-14 arylcarbamoyloxy which may be substituted;

(24) heterocyclic oxy which can be substituted;

(25) a C1-10 alkylsulfonyloxy group which may be substituted;

(26) mercapton group;

(27) C1-10 alkylsulfanyl which may be substituted;

(28) a C3-7 cycloalkylsulfanyl group which may be substituted;

(29) C6-14 arylsulfanyl which may be substituted;

(30) a C7-16 aralkylsulfanyl group which may be substituted;

(31) heterocyclic sulfanyl group which may be substituted;

(32) formyl group;

(33) a C1-10 alkylcarbonyl group which may be substituted;

(34) a C3-7 cycloalkylcarbonyl group which may be substituted;

(35) C6-14 arylcarbonyl group which may be substituted;

(36) a C7-16 aralkylcarbonyl group which may be substituted;

(37) heterocyclic carbonyl group which may be substituted;

(38) a C 1-10 alkylsulfonyl group which may be substituted;

(39) a C3-7 cycloalkylsulfonyl group which may be substituted;

(40) C6-14 arylsulfonyl which may be substituted;

(41) heterocyclic sulfonyl group which may be substituted;

(42) a C 1-10 alkylsulfinyl group which may be substituted;

(43) a C3-7 cycloalkylsulfinyl group which may be substituted;

(44) C6-14 arylsulfinyl which may be substituted;

(45) heterocyclic sulfinyl group which may be substituted;

(46) sulfone group;

(47) sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) thiocarbamoyl group;

(51) carbamoyl group which may be substituted;

(52) amino, mono- or di-C1-10 alkylamino which may be substituted, mono- or di-C3-7 cycloalkylamino which may be substituted, mono- or di-C6-14 arylamino which may be substituted, a mono- or di-C7-16 aralkylamino group which may be substituted, a heterocyclic amino group which may be substituted, a C6-14 arylcarbonylamino group which may be substituted, a formylamino group, a C1-10 alkylcarbonylamino group, which may be substituted, a C3-7 cycloalkylcarbonylamino group which may be substituted, a heterocyclic carbonylamino group which may be substituted, a C3-7 cycloalkyloxycarbonylamino group which may be substituted, a heterocyclic oxycarbonylamino group which may be substituted, a carbamoylamino group which may be substituted, a C1-10 alkylsulfonylamino group which may be substituted, a C3-7 cycloalkylsulfonylamino group which may be substituted, heterocyclic sulfonylamino group which may be substituted, C6-14 arylsulfonylamino group which may be substituted, and among the above-mentioned group A substituents, "C1-10 alkoxycarbonyl group which may be substituted", "C1-10 alkyl group which may be substituted "," a C2-6 alkenyl group which may be substituted "," a C2-6 alkynyl group which may be substituted "," a C1-10 alkoxy group which may be substituted "," a C1-10 alkylcarbonyloxy group, which may be substituted, "" C1-10 alkoxycarbonyloxy which may be substituted, "" mono-C1-10 alkylcarbamoyloxy, which may be substituted, "" di and C1-10 alkylcarbamoyloxy, which may be substituted, "" C1-10 alkylsulfanyl which may be substituted, "" C1-10 alkylcarbonyl which may be substituted "," C1-10 alkylsulfonyl which may be substituted "," C1-10 alkylsulfinyl which may be substituted ", "C1-10 alkylcarbamoyl group which may be substituted", "mono- or di-C1-10 alkylamino group which may be substituted", "C1-10 alkylcarbonylamino group which may be substituted", "mono- (C1 -10 alkylcarbonyl) amino which may be substituted, "" C1-10 alkoxycarbonylamino which may be substituted ", and" C1-10 alkylsulfonylamino which may be substituted ", the substituents of which may be selected from the following group B substituents, wherein the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3, [Group B substituents] [0014] (a) a halogen atom;

(b) a hydroxyl group;

(c) nitro;

(d) cyano;

(e) a C6-14 aryl group which may be substituted;

(f) a C6-14 aryloxy group which may be substituted;

(g) a C7-16 aralkyloxy group which may be substituted;

(h) a mono- or di-5- to 10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group which may be substituted;

(j) a C3-7 cycloalkyl group;

(k) a C1-10 alkoxy group which may be substituted;

(1) formyl group;

(m) C1-10 alkylcarbonyl;

(n) C 3-7 cycloalkylcarbonyl;

(o) C6-14 arylcarbonyl;

(p) a C7-16 aralkylcarbonyl group;

(q) a C 1-10 alkoxycarbonyl group;

(r) C6-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl group;

(t) C1-10 alkylsulfanyl;

(u) a C 1-10 alkylsulfinyl group;

(v) a C 1-10 alkylsulfonyl group;

(w) carbamoyl group;

(x) thiocarbamoyl group;

(y) mono-C 1-10 alkylcarbamoyl group;

(z) di-C 1-10 alkylcarbamoyl group;

(aa) mono- or di-C6-14 arylcarbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic carbamoyl group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and among the above-mentioned group A of substituents, the "C6-14 aryloxycarbonyl group, which may be substituted "," C7-16 aralkyloxycarbonyl group which may be substituted "," C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted "," C3-7 cycloalkyl group which may be substituted "," group C6-14 aryl, which may be substituted "," C7-16 aralkyl group which may be substituted "," C6-14 aryl-C2-6 alkenyl group which may be substituted "," heterocyclic group which may be substituted "," group C3 -7 cycloalkyloxy which may be substituted "," C6-14 aryloxy which may be substituted "," C7-16 aralkyloxy which may be substituted "," C6-14 arylcarbonyloxy which may be substituted "," mono- or di-C6-14 arylcarbamoyloxy group, which may be substituted "," a heterocyclic oxy group which may be substituted "," an aromatic heterocyclic oxy group which may be substituted "," a C3-7 cycloalkylsulfanyl group which may be substituted "," a C6-14 arylsulfanyl group which may be substituted, "" C7-16 aralkylsulfanyl which may be substituted, "" heterocyclic sulfanyl which may be substituted, "" C3-7 cycloalkylcarbonyl, which may be substituted, " "C6-14 arylcarbonyl group which may be substituted", "C7-16 aralkylcarbonyl group which may be substituted", "heterocyclic carbonyl group which may be substituted", "C3-7 cycloalkylsulfonyl group which may be substituted", "C6-14 arylsulfonyl group which may be substituted", "heterocyclic sulfonyl group which may be substituted", "C3-7 cycloalkylsulfinyl group which may be substituted", "C6-14 arylsulfinyl group, which may be substituted "," a heterocyclic sulfinyl group which may be substituted "," a carbamoyl group which may be substituted "," an amino group which may be substituted "," a mono or di-C3-7 cycloalkylamino group which may be substituted, "" mono- or di-C6-14 arylamino, which may be substituted, "" mono- or di-C7-16 aralkylamino, which may be substituted, "" heterocyclic amino, which may be substituted "," C6-14 arylcarbonylamino group, which may be substituted "," a C3-7 cycloalkylcarbonylamino group which may be substituted "," a heterocyclic carbonylamino group which may be substituted "," a C3-7 cycloalkyloxycarbonylamino group which may be substituted "," a heterocyclic oxycarbonylamino group which may be substituted "," a carbamoylamino group which may be substituted "," an alkylsulfonylamino group which may be substituted "," a C3-7 cycloalkylsulfonylamino group which may be substituted ", A "heterocyclic sulfonylamino group which may be substituted", and a "C6-14 arylsulfonylamino group which may be substituted" whose substituents may be selected from the above-mentioned group B substituents and the following group B 'substituents, the number of substituents being in a range of 1 to the maximum number that can be substituted, more preferably 1 to 3 substituents:

[Group B 'substituents] [0015] (a) a C1-10 alkyl group which may be substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino group, mono- or di-C6-14 arylamino, monol or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

(b) a C2-6 alkenyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino group , mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl; and (c) a C2-6 alkynyl group which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl; or its salt.

[2] The compound according to the above-mentioned [1], in which

R² is a halogen atom, a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted.

[3] The compound according to the above-mentioned [2], wherein R² is a C1-10 alkoxy group which may be substituted by one or more substituents selected from a halogen atom, a C1-10 alkoxy group, and a C3-7 cycloalkyl group.

[4] The compound according to the above-mentioned [2], in which R² is a C1-10 alkoxy group.

[5] The compound according to the above-mentioned [2], wherein R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group which may be substituted and a C1-10 alkoxy group which may be substituted.

[6] The compound according to the above-mentioned [2], in which R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group and a C1-10 alkoxy group.

[7] The compound according to the above-mentioned [2], wherein R¹ is a phenyl group which may be substituted by 1 to 5 halogen atoms.

o [8] The compound according to the above-mentioned [2], wherein R³ represents a hydrogen atom or a C 1-10 alkoxy group which may be substituted.

ο [9] The compound according to the above-mentioned [2], in which R³ represents a hydrogen atom or a C 1-10 alkoxy group.

β [10] The compound according to the above-mentioned [2], wherein R³ is hydrogen.

[11] A compound according to the above-mentioned [2], wherein ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted , (3) a C1-10 alkoxy group which may be substituted, (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom, and 1 to 3 nitrogen atoms as heteroatoms that can be substituted, ( 5) C1-10 alkylsulfonyl group, which may be substituted, (6) a C3-7 cycloalkyl group which may be substituted, (7) a cyano group, (8) a carbamoyl group which may be substituted, (9) a C1-10 alkylsulfonyloxy group which may be substituted, (10) C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted, (11) tetrahydropyranyl group which may be substituted, (12) dihydropyranyl group which may be substituted, (13) mono- (C1- 10-alkylcarbonyl) amino which may be substituted, (14) a C1-10 alkoxycarbonyl group which may be substituted, (15) a C1-10 alkylsulfinyl group which may be substituted, and (16) a C1-10 alkylsulfanyl group which may be substituted.

[12] A compound according to the above-mentioned [2], wherein ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted , (3) a C1-10 alkoxy group which may be substituted, (4) a C3-7 cycloalkyl group, (5) a halogen C1-10 alkylsulfonyloxy group, (6) a C3-7 cycloalkyl C2-6 alkynyl group, and (7) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by one or more substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that may be substituted, and a C 1-10 alkyl group that may be substituted.

[13] A compound according to the above-mentioned [2], wherein ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted by 1 to 3 halogen atoms, (3) C1-10 alkoxy group, which may be substituted by 1 to 3 halogen atoms, (4) C3-7 cycloalkyl group, (5) C1-10 halogenosulfonyloxy group, (6) groups C3-7 cycloalkyl-C2-6 alkynyl, and (7) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, hydroxyl group, oxo group, group A C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that may be substituted by a halogen atom, and a C 1-10 alkyl group that may be substituted by a halogen atom.

[14] A compound according to the above-mentioned [2], wherein ring A is a benzene ring which is substituted with (1) (i) 1 or 2 halogen atoms, or (ii) one C1-10 alkoxy group, and (2 ) one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom, and from 1 to 3 nitrogen atoms, as heteroatoms, which can be substituted by 1 to 4 substituents selected from halogen, hydroxyl group, oxo group, C1 group -10 alkoxycarbonyl, a C 1-10 alkoxy group which may be substituted by a halogen atom and a C 1-10 alkyl group which may be substituted by a halogen atom.

[15] The compound according to the above-mentioned [14], in which a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms means a morpholine group, a pyrrolyl group, a dihydropyrrolyl group, a pyrazolyl group , dihydropyrazolyl group, piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group or imidazolidinyl group.

[16] A compound according to the above-mentioned [2], wherein ring B is an imidazole ring, pyrazole ring, triazole ring or tetrazole ring, each of which may be further substituted with from 1 to 3 substituents selected from halogen, and C1 -10 alkyl which may be substituted by a halogen atom.

[17] The compound of the above-mentioned [2], wherein ring B is a pyrazole ring which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom.

[18] A compound according to the above-mentioned [2], wherein ring B is a pyrazole ring.

[19] The compound according to the above-mentioned [2], in which

R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group which may be substituted and a C1-10 alkoxy group which may be substituted,

R² is a halogen atom, a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted,

R³ is a hydrogen atom or a C 1-10 alkoxy group which may be substituted, ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-10 alkyl group which may be substituted, (3) C1-10 alkoxy which may be substituted, (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom, and from 1 to 3 nitrogen atoms as heteroatoms which may be substituted, (5) C1-10 alkylsulfonyl which may be substituted, (6) C3-7 cycloalkyl which may be substituted, (7) cyano, (8) carbamoyl which may be substituted, (9) C1 -10 alkylsulfonyloxy which may be substituted, (10) C3-7 cycloalkyl-C2-6 alkynyl which may be substituted, (11) tetrahydropyranyl which may be substituted, (12) dihydropyranyl which may be substituted, (13) mono- (C1-10 alkylcarbonyl) amino which may be substituted, (14) C1-10 alkoxycarbonyl which may be substituted, (15) C1-10 alkylsulfinyl which may be substituted, and (16) ) a C1-10 alkylsulfanyl group which may be substituted, and ring B is an imidazole ring, pyrazole ring, triazole ring or tetrazole ring, each of which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom.

[20] A compound according to the above-mentioned [19], wherein ring A is a benzene ring which can be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group that can be substituted , (3) a C1-10 alkoxy group which may be substituted, (4) a C3-7 cycloalkyl group, (5) a halogen C1-10 alkylsulfonyloxy group, (6) a C3-7 cycloalkyl C2-6 alkynyl group, and (7) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by one or more substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that may be substituted, and a C 1-10 alkyl group that may be substituted.

[21] The compound according to the above-mentioned [2], in which

R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group and a C1-10 alkoxy group,

R² is a C1-10 alkoxy group which may be substituted by one or more substituents selected from a halogen atom, a C1-10 alkoxy group and a C3-7 cycloalkyl group,

R³ is a hydrogen atom or a C1-10 alkoxy group, ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted by 1 to 3 halogen atoms, (3) C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms, (4) C3-7 cycloalkyl group, (5) halogen C1-10 alkylsulfonyloxy group, (6) C3-7 cycloalkyl-C2-6 alkynyl group and (7) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom, and from 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that can be substituted by a halogen atom, and a C 1-10 alkyl group that can be substituted by a halogen atom, ring B is a pyrazole ring which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom.

[22] The compound according to the above-mentioned [2], in which

R¹ is a phenyl group which may be substituted by 1 to 5 halogen atoms,

R² is a C1-10 alkoxy group, ο

R³ is hydrogen, ring A is a benzene ring which is substituted by (1) (i) 1 or 2 halogen atoms or (ii) one C1-10 alkoxy group, and (2) one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C1-10 alkoxycarbonyl group, a C1-10 alkoxy group, which can be substituted by a halogen atom and a C1-10 alkyl group that can be substituted by a halogen atom, ring B is a pyrazole ring.

[23] The compound according to the above-mentioned [22], in which a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms, as heteroatoms, means a morpholine group, a pyrrolyl group, a dihydropyrrolyl group, a pyrazolyl group , dihydropyrazolyl group, piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group or imidazolidinyl group.

[24] The compound according to the above-mentioned [1], in which

R¹ is an aromatic group which may be substituted, ring A is an aromatic ring which is substituted by (a) one substituent selected from (1) a C3-7 cycloalkyl group which may be substituted, and (2) 4- to 6-membered a heterocyclic group containing from 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom that can be substituted, and (b) one or more additional substituents.

[25] The compound according to the above-mentioned [24], in which

R¹ is a phenyl group which may be substituted

R² is a halogen atom, a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted,

R³ is a hydrogen atom or a C 1-10 alkoxy group which may be substituted, ring A is a benzene ring which is substituted by one substituent selected from (1) a C 3-7 cycloalkyl group which may be substituted, (2) a dihydropyranyl group which may be substituted, (3) a tetrahydropyranyl group which may be substituted, and (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which may be substituted, and may be substituted by additional substituents, and ring B is an imidazole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, 1,3-oxazole ring, furan ring or thiophene ring, each of which may be substituted.

[26] The compound according to the above-mentioned [25], in which a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms, as heteroatoms, means a morpholine group, a pyrrolyl group, a dihydropyrrolyl group, a pyrazolyl group , dihydropyrazolyl group, piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group, imidazolidinyl group, isoxazolyl group, pyridyl group, a piperazinyl group or a thiazolyl group.

[27] The compound according to the above-mentioned [24], in which the additional substituents are from 1 to 4 substituents selected from (1) a halogen atom, (2) an oxo group, (3) a hydroxyl group, (4) a C1-10 alkyl group which may be substituted, (5) a C1-10 alkoxy group which may be substituted, (6) a C1-10 alkylsulfonyl group, (7) a morpholin-4-ylsulfonyl group, (8) a cyano group, (9) a carbamoyl group , (10) C 1-10 alkylsulfonyloxy group, (11) C3-7 cycloalkyl-C2-6 alkynyl group, (12) di-C1-10 alkylamino group, (13) mono- (C1-10 alkylcarbonyl) amino group, (14) C1-10 alkoxycarbonyl group, (15) ) phenoxy, (16) C1-10 alkylsulfinyl, (17) benzimidazol-2-yloxy, and (18) benzimidazol-2-ylsulfonyl.

[28] The compound according to the above-mentioned [24], in which

R¹ is a phenyl group which may be substituted by 1 to 5 halogen atoms,

R² is C1-10 alkoxy, o

R³ is a hydrogen atom, ring A is a benzene ring which is substituted by one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from atom halogen, hydroxyl group, oxo group, C1-10 alkoxy halogen group, C1-10 alkoxycarbonyl group and C1-10 alkyl group, which may be substituted by a halogen atom and which may be further substituted by 1 or 2 substituents selected from a halogen atom and a C1-10 alkoxy group, and ring B is a pyrazole ring.

[29] The compound according to the above-mentioned [28], in which a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms, as heteroatoms, means a morpholine group, a pyrrolyl group, a dihydropyrrolyl group, a pyrazolyl group , dihydropyrazolyl group, piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group or imidazolidinyl group.

[30] The compound according to the above-mentioned [1], which is 1- [2-fluoro-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl) -1H-pyrazol-5-yl) pyridazin-4 (1H) -one or a salt thereof.

[31] The compound according to the above-mentioned [1], which is 1- [2-fluoro-4- (2-oxopyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5- yl) pyridazine-4 (1H) -one or a salt thereof.

[32] The compound according to the above-mentioned [1], which is 1- [4- (3,4-difluoro1H-pyrrol-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H pyrazol-5-yl) pyridazin-4 (1H) he or a salt thereof.

[33] The compound according to the above-mentioned [1], which is 1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5- yl) pyridazine-4 (1H) -one or a salt thereof.

[34] The compound according to the above-mentioned [1], which is 1- [4- (4-chloro-1H-pyrazol-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazole -5-yl) pyridazin-4 (1H) he or a salt thereof.

[35] The compound according to the above-mentioned [1], which is 1- [2-fluoro-4- (2-oxo-1,3-oxazolidin-3-yl) phenyl] -5-methoxy-3- (1-phenyl- 1H-pyrazol-5-yl) pyridazine-4 (1H) -one or a salt thereof.

[36] The compound according to the above-mentioned [1], which is 3- [1- (2-fluoro-phenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine-4 (1H) -one or a salt thereof.

[37] The compound according to the above-mentioned [1], which is 3- [1- (3-chlorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine-4 (1H) -one or a salt thereof.

[38] The compound according to the above-mentioned [1] which is 1- [4- (4,4-dimethyl-2-oxopyrrolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H pyrazol-5-yl) pyridazine-4 (1H) -one or a salt thereof.

[39] The compound according to the above-mentioned [1], which is 1- [4- (5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one or a salt thereof.

[40] The compound according to the above-mentioned [1], which is 5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5- yl) pyridazine-4 (1H) -one or a salt thereof.

[41] A medicine containing the compound according to the above-mentioned items [1] to [40].

[42] Drug according to the above-mentioned [41] for use in inhibiting phosphodiesterase 10A.

[43] The drug according to the above-mentioned [41] for use in the prevention or treatment of schizophrenia, autism, Alzheimer's disease, bipolar disorder, Parkinson's disease, Huntington's disease, obesity, drug addiction or attention deficit / hyperactivity disorder.

[44] Use of the compound of formula (I0):

<img file="PL2393360T3_D0004.tif" />

wherein

R¹ is a substituent

R² is a substituent, β

R³ is a hydrogen atom or a substituent, ring A is an aromatic ring that can be substituted and ring B is a 5-membered heteroaromatic ring that can be substituted,

3 in which substituents for R¹, R² or R³, the "aromatic ring which may be substituted" for ring A or the substituents of the "5-membered heteroaromatic ring which may be substituted" for ring B are selected from the group A of substituents;

[Group A substituents] [0016] (1) a halogen atom;

(2) nitro group;

(3) cyano group;

(4) a carboxy group that can be esterified;

(5) C1-10 alkyl which may be substituted;

(6) a C2-6 alkenyl group which may be substituted;

(7) a C2-6 alkynyl group which may be substituted;

(8) a C3-7 cycloalkyl group which may be substituted;

(9) C6-14 aryl which may be substituted;

(10) a C7-16 aralkyl group which may be substituted;

(11) C6-14 aryl-C2-6 alkenyl which may be substituted;

(12) heterocyclic group which may be substituted;

(13) hydroxyl group;

(14) a C1-10 alkoxy group which may be substituted;

(15) a C3-7 cycloalkyloxy group which may be substituted;

(16) C6-14 aryloxy which may be substituted;

(17) a C7-16 aralkyloxy group which may be substituted;

(18) a C1-10 alkylcarbonyloxy group which may be substituted;

(19) a C1-10 alkoxycarbonyloxy group which may be substituted;

(20) mono-C 1-10 alkylcarbamoyloxy group which may be substituted;

(21) di-C 1-10 alkylcarbamoyloxy which may be substituted;

(22) C6-14 arylcarbonyloxy group which may be substituted;

(23) mono- or di-C6-14 arylcarbamoyloxy which may be substituted;

(24) heterocyclic oxy which can be substituted;

(25) a C1-10 alkylsulfonyloxy group which may be substituted;

(26) mercapton group;

(27) C1-10 alkylsulfanyl which may be substituted;

(28) a C3-7 cycloalkylsulfanyl group which may be substituted;

(29) C6-14 arylsulfanyl which may be substituted;

(30) a C7-16 aralkylsulfanyl group which may be substituted;

(31) heterocyclic sulfanyl group which may be substituted;

(32) formyl group;

(33) a C1-10 alkylcarbonyl group which may be substituted;

(34) a C3-7 cycloalkylcarbonyl group which may be substituted;

(35) C6-14 arylcarbonyl group which may be substituted;

(36) a C7-16 aralkylcarbonyl group which may be substituted;

(37) heterocyclic carbonyl group which may be substituted;

(38) a C 1-10 alkylsulfonyl group which may be substituted;

(39) a C3-7 cycloalkylsulfonyl group which may be substituted;

(40) C6-14 arylsulfonyl which may be substituted;

(41) heterocyclic sulfonyl group which may be substituted;

(42) a C 1-10 alkylsulfinyl group which may be substituted;

(43) a C3-7 cycloalkylsulfinyl group which may be substituted;

(44) C6-14 arylsulfinyl which may be substituted;

(45) heterocyclic sulfinyl group which may be substituted;

(46) sulfone group;

(47) sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) thiocarbamoyl group;

(51) carbamoyl group which may be substituted;

(52) amino, mono- or di-C 1-10 alkylamino which may be substituted, mono or di-C 3-7 cycloalkylamino which may be substituted, mono- or di-C 6-14 arylamino which may be substituted, a mono- or di-C7-16 aralkylamino group which may be substituted, a heterocyclic amino group which may be substituted, a C6-14 arylcarbonylamino group which may be substituted, a formylamino group, a C1-10 alkylcarbonylamino group, which may be substituted, a C3-7 cycloalkylcarbonylamino group which may be substituted, a heterocyclic carbonylamino group which may be substituted, a C3-7 cycloalkyloxycarbonylamino group which may be substituted, a heterocyclic oxycarbonylamino group which may be substituted, a carbamoylamino group which may be substituted, a C1-10 alkylsulfonylamino group which may be substituted, a C3-7 cycloalkylsulfonylamino group which may be substituted, heterocyclic sulfonylamino group which may be substituted, C6-14 arylsulfonylamino group which may be substituted, and among the above-mentioned group A substituents, "C1-10 alkoxycarbonyl group which may be substituted", "C1-10 alkyl group which may be substituted "," a C2-6 alkenyl group which may be substituted "," a C2-6 alkynyl group which may be substituted "," a C1-10 alkoxy group which may be substituted "," a C1-10 alkylcarbonyloxy group, which may be substituted "," C1-10 alkoxycarbonyloxy group which may be substituted "," mono-C1-10 alkylcarbamoyloxy group which may be substituted "," di and C1-10 alkylcarbamoyloxy group which may be substituted "," group C1-10 alkylsulfanyl which may be substituted, "" C1-10 alkylcarbonyl which may be substituted "," C1-10 alkylsulfonyl which may be substituted "," C1-10 alkylsulfinyl which may be substituted ", "C1-10 alkylcarbamoyl group which may be substituted", "mono- or di-C1-10 alkylamino group which may be substituted", "C1-10 alkylcarbonylamino group which may be substituted", "mono (C1 -10 alkylcarbonyl) amino which may be substituted, "" C1-10 alkoxycarbonylamino which may be substituted "and" C1-10 alkylsulfonylamino which may be substituted ", the substituents of which may be selected from the following group of B substituents, wherein the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3, [Group B substituents] [0017] (a) a halogen atom;

(b) a hydroxyl group;

(c) nitro;

(d) cyano;

(e) a C6-14 aryl group which may be substituted;

(f) a C6-14 aryloxy group which may be substituted;

(g) a C7-16 aralkyloxy group which may be substituted;

(h) a mono- or di-5- to 10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group which may be substituted;

(j) a C3-7 cycloalkyl group;

(k) a C1-10 alkoxy group which may be substituted;

(1) formyl group;

(m) C1-10 alkylcarbonyl;

(n) C 3-7 cycloalkylcarbonyl;

(o) C6-14 arylcarbonyl;

(p) a C7-16 aralkylcarbonyl group;

(q) a C 1-10 alkoxycarbonyl group;

(r) C6-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl group;

(t) C1-10 alkylsulfanyl;

(u) a C 1-10 alkylsulfinyl group;

(v) a C 1-10 alkylsulfonyl group;

(w) carbamoyl group;

(x) thiocarbamoyl group;

(y) mono-C 1-10 alkylcarbamoyl group;

(z) di-C 1-10 alkylcarbamoyl group;

(aa) mono- or di-C6-14 arylcarbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic carbamoyl group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and among the above-mentioned group A of substituents, the "C6-14 aryloxycarbonyl group, which may be substituted "," C7-16 aralkyloxycarbonyl group which may be substituted "," C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted "," C3-7 cycloalkyl group which may be substituted "," group C6-14 aryl, which may be substituted "," C7-16 aralkyl group which may be substituted "," C6-14 aryl-C2-6 alkenyl group which may be substituted "," heterocyclic group which may be substituted "," group C3 -7 cycloalkyloxy which may be substituted "," C6-14 aryloxy which may be substituted "," C7-16 aralkyloxy which may be substituted "," C6-14 arylcarbonyloxy which may be substituted "," mono- or di-C6-14 arylcarbamoyloxy group, which may be substituted "," a heterocyclic oxy group which may be substituted "," an aromatic heterocyclic oxy group which may be substituted "," a C3-7 cycloalkylsulfanyl group which may be substituted "," a C6-14 arylsulfanyl group which may be substituted, "" C7-16 aralkylsulfanyl which may be substituted, "" heterocyclic sulfanyl which may be substituted, "" C3-7 cycloalkylcarbonyl, which may be substituted, " "C6-14 arylcarbonyl group which may be substituted", "C7-16 aralkylcarbonyl group which may be substituted", "heterocyclic carbonyl group which may be substituted", "C3-7 cycloalkylsulfonyl group which may be substituted", "C6-14 arylsulfonyl group which may be substituted", "heterocyclic sulfonyl group which may be substituted", "C3-7 cycloalkylsulfinyl group which may be substituted", "C6-14 arylsulfinyl group, which may be substituted "," a heterocyclic sulfinyl group which may be substituted "," a carbamoyl group which may be substituted "," an amino group which may be substituted "," a mono or di-C3-7 cycloalkylamino group which may be substituted, "" mono- or di-C6-14 arylamino, which may be substituted, "" mono- or di-C7-16 aralkylamino, which may be substituted, "" heterocyclic amino, which may be substituted "," C6-14 arylcarbonylamino group, which may be substituted "," a C3-7 cycloalkylcarbonylamino group which may be substituted "," a heterocyclic carbonylamino group which may be substituted "," a C3-7 cycloalkyloxycarbonylamino group which may be substituted "," a heterocyclic oxycarbonylamino group which may be substituted "," a carbamoylamino group which may be substituted "," an alkylsulfonylamino group which may be substituted "," a C3-7 cycloalkylsulfonylamino group which may be substituted ", A "heterocyclic sulfonylamino group which may be substituted" and a "C6-14 arylsulfonylamino group which may be substituted" whose substituents may be selected from the above-mentioned group B substituents and the following group B 'substituents, the number of substituents being in the range from 1 to a maximum number that can be substituted, more preferably from 1 to 3 substituents:

[Group B 'of substituents] [0018] (a) a C1-10 alkyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino group, mono- or di-C6-14 arylamino, monol or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

(b) a C2-6 alkenyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino group , mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl; and (c) a C2-6 alkynyl group which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

or a salt thereof, for the manufacture of a medicament for the prevention or treatment of schizophrenia, autism, Alzheimer's disease, bipolar disorder, Parkinson's disease, Huntington's disease, obesity, drug addiction or attention deficit / hyperactivity disorder.

[45] Compound of formula (I0):

<img file="PL2393360T3_D0005.tif" />

wherein

R¹ is a substituent

R² is a substituent, β

R³ is a hydrogen atom or a substituent, ring A is an aromatic ring that can be substituted and ring B is a 5-membered heteroaromatic ring that can be substituted,

3 wherein the substituent for R¹, R² or R³, the substituents of the "aromatic ring that can be substituted" for ring A or the substituents of the "5-membered heteroaromatic ring that can be substituted" for ring B are selected from group A of substituents;

[Group A substituents] [0019] (1) a halogen atom;

(2) nitro group;

(3) cyano group;

(4) a carboxy group that can be esterified;

(5) C1-10 alkyl which may be substituted;

(6) a C2-6 alkenyl group which may be substituted;

(7) a C2-6 alkynyl group which may be substituted;

(8) a C3-7 cycloalkyl group which may be substituted;

(9) C6-14 aryl which may be substituted;

(10) a C7-16 aralkyl group which may be substituted;

(11) C6-14 aryl-C2-6 alkenyl which may be substituted;

(12) heterocyclic group which may be substituted;

(13) hydroxyl group;

(14) a C1-10 alkoxy group which may be substituted;

(15) a C3-7 cycloalkyloxy group which may be substituted;

(16) C6-14 aryloxy which may be substituted;

(17) a C7-16 aralkyloxy group which may be substituted;

(18) a C1-10 alkylcarbonyloxy group which may be substituted;

(19) a C1-10 alkoxycarbonyloxy group which may be substituted;

(20) mono-C 1-10 alkylcarbamoyloxy group which may be substituted;

(21) di-C 1-10 alkylcarbamoyloxy which may be substituted;

(22) C6-14 arylcarbonyloxy group which may be substituted;

(23) mono- or di-C6-14 arylcarbamoyloxy which may be substituted;

(24) heterocyclic oxy which can be substituted;

(25) a C1-10 alkylsulfonyloxy group which may be substituted;

(26) mercapton group;

(27) C1-10 alkylsulfanyl which may be substituted;

(28) a C3-7 cycloalkylsulfanyl group which may be substituted;

(29) C6-14 arylsulfanyl which may be substituted;

(30) a C7-16 aralkylsulfanyl group which may be substituted;

(31) heterocyclic sulfanyl group which may be substituted;

(32) formyl group;

(33) a C1-10 alkylcarbonyl group which may be substituted;

(34) a C3-7 cycloalkylcarbonyl group which may be substituted;

(35) C6-14 arylcarbonyl group which may be substituted;

(36) a C7-16 aralkylcarbonyl group which may be substituted;

(37) heterocyclic carbonyl group which may be substituted;

(38) a C 1-10 alkylsulfonyl group which may be substituted;

(39) a C3-7 cycloalkylsulfonyl group which may be substituted;

(40) C6-14 arylsulfonyl which may be substituted;

(41) heterocyclic sulfonyl group which may be substituted;

(42) a C 1-10 alkylsulfinyl group which may be substituted;

(43) a C3-7 cycloalkylsulfinyl group which may be substituted;

(44) C6-14 arylsulfinyl which may be substituted;

(45) heterocyclic sulfinyl group which may be substituted;

(46) sulfone group;

(47) sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) thiocarbamoyl group;

(51) carbamoyl group which may be substituted;

(52) amino, mono- or di-C 1-10 alkylamino which may be substituted, mono or di-C 3-7 cycloalkylamino which may be substituted, mono- or di-C 6-14 arylamino which may be substituted, a mono- or di-C7-16 aralkylamino group which may be substituted, a heterocyclic amino group which may be substituted, a C6-14 arylcarbonylamino group which may be substituted, a formylamino group, a C1-10 alkylcarbonylamino group, which may be substituted, a C3-7 cycloalkylcarbonylamino group which may be substituted, a heterocyclic carbonylamino group which may be substituted, a C3-7 cycloalkyloxycarbonylamino group which may be substituted, a heterocyclic oxycarbonylamino group which may be substituted, a carbamoylamino group which may be substituted, a C1-10 alkylsulfonylamino group which may be substituted, a C3-7 cycloalkylsulfonylamino group which may be substituted, heterocyclic sulfonylamino group which may be substituted, C6-14 arylsulfonylamino group which may be substituted, and among the above-mentioned group A substituents, "C1-10 alkoxycarbonyl group which may be substituted", "C1-10 alkyl group which may be substituted "," a C2-6 alkenyl group which may be substituted "," a C2-6 alkynyl group which may be substituted "," a C1-10 alkoxy group which may be substituted "," a C1-10 alkylcarbonyloxy group, which may be substituted "," C1-10 alkoxycarbonyloxy group which may be substituted "," mono-C1-10 alkylcarbamoyloxy group which may be substituted "," di and C1-10 alkylcarbamoyloxy group which may be substituted "," group C1-10 alkylsulfanyl which may be substituted, "" C1-10 alkylcarbonyl which may be substituted "," C1-10 alkylsulfonyl which may be substituted "," C1-10 alkylsulfinyl which may be substituted ", "C1-10 alkylcarbamoyl group which may be substituted", "mono- or di-C1-10 alkylamino group which may be substituted", "C1-10 alkylcarbonylamino group which may be substituted", "mono (C1 -10 alkylcarbonyl) amino which may be substituted, "" C1-10 alkoxycarbonylamino which may be substituted "and" C1-10 alkylsulfonylamino which may be substituted ", the substituents of which may be selected from the following group of B substituents, wherein the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3, [Group B substituents] [0020] (a) a halogen atom;

(b) a hydroxyl group;

(c) nitro;

(d) cyano;

(e) a C6-14 aryl group which may be substituted;

(f) a C6-14 aryloxy group which may be substituted;

(g) a C7-16 aralkyloxy group which may be substituted;

(h) a mono- or di-5- to 10-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group which may be substituted;

(j) a C3-7 cycloalkyl group;

(k) a C1-10 alkoxy group which may be substituted;

(1) formyl group;

(m) C1-10 alkylcarbonyl;

(n) C 3-7 cycloalkylcarbonyl;

(o) C6-14 arylcarbonyl;

(p) a C7-16 aralkylcarbonyl group;

(q) a C 1-10 alkoxycarbonyl group;

(r) C6-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl group;

(t) C1-10 alkylsulfanyl;

(u) a C 1-10 alkylsulfinyl group;

(v) a C 1-10 alkylsulfonyl group;

(w) carbamoyl group;

(x) thiocarbamoyl group;

(y) mono-C 1-10 alkylcarbamoyl group;

(z) di-C 1-10 alkylcarbamoyl group;

(aa) mono- or di-C6-14 arylcarbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic carbamoyl group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and among the above-mentioned group A of substituents, the "C6-14 aryloxycarbonyl group, which may be substituted "," C7-16 aralkyloxycarbonyl group which may be substituted "," C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted "," C3-7 cycloalkyl group which may be substituted "," group C6-14 aryl, which may be substituted "," C7-16 aralkyl group which may be substituted "," C6-14 aryl-C2-6 alkenyl group which may be substituted "," heterocyclic group which may be substituted "," group C3 -7 cycloalkyloxy which may be substituted "," C6-14 aryloxy which may be substituted "," C7-16 aralkyloxy which may be substituted "," C6-14 arylcarbonyloxy which may be substituted "," mono- or di-C6-14 arylcarbamoyloxy group, which can be substituted, "" an heterocyclic oxy group that can be substituted, "" an aromatic heterocyclic oxy group, which can be substituted, "" a C3-7 cycloalkylsulfanyl group that can be substituted, "" a C6-14 arylsulfanyl group, which may be substituted, "" C7-16 aralkylsulfanyl which may be substituted, "" heterocyclic sulfanyl, which may be substituted, "" C3-7 cycloalkylcarbonyl, which may be substituted, " "C6-14 arylcarbonyl group which may be substituted", "C7-16 aralkylcarbonyl group which may be substituted", "heterocyclic carbonyl group which may be substituted", "C3-7 cycloalkylsulfonyl group which may be substituted", "C6-14 arylsulfonyl group which may be substituted", "heterocyclic sulfonyl group which may be substituted", "C3-7 cycloalkylsulfinyl group which may be substituted", "C6-14 arylsulfinyl group, which may be substituted "," a heterocyclic sulfinyl group which may be substituted "," a carbamoyl group which may be substituted "," an amino group which may be substituted "," a mono or di-C3-7 cycloalkylamino group which may be substituted, "" mono- or di-C6-14 arylamino, which may be substituted, "" mono- or di-C7-16 aralkylamino, which may be substituted, "" heterocyclic amino, which may be substituted "," C6-14 arylcarbonylamino group, which may be substituted "," a C3-7 cycloalkylcarbonylamino group which may be substituted "," a heterocyclic carbonylamino group which may be substituted "," a C3-7 cycloalkyloxycarbonylamino group which may be substituted "," a heterocyclic oxycarbonylamino group which may be substituted "," a carbamoylamino group which may be substituted "," an alkylsulfonylamino group which may be substituted "," a C3-7 cycloalkylsulfonylamino group which may be substituted ", A "heterocyclic sulfonylamino group which may be substituted" and a "C6-14 arylsulfonylamino group which may be substituted" whose substituents may be selected from the above-mentioned group B substituents and the following group B 'substituents, the number of substituents being in the range from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents:

[Group B 'of substituents] [0021] (a) a C1-10 alkyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino group, mono- or di-C6-14 arylamino, monol or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

(b) a C2-6 alkenyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino group , monol or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl; and (c) a C2-6 alkynyl group which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

or a salt thereof, for use in the prevention or treatment of schizophrenia, autism, Alzheimer's disease, bipolar disorder, Parkinson's disease, Huntington's disease, obesity, drug addiction or attention deficit / hyperactivity disorder.

Advantageous Effects of the Invention [0022] The compound of the present invention has PDE inhibitory activity and is useful as a medicament for the prevention or treatment of schizophrenia.

Brief description of the drawings [0023]

Fig. 1. Graph showing dose-dependent increases in cAMP (Fig. 1A) and cGMP (Fig. 1B) in the striatum of mouse using comparative compound A.

Fig. 2. Graph showing dose-dependent inhibition of methamphetamine-induced hyperactivity (MAP) - or MK-801 by reference compound A. Comparative compound A reduced spontaneous movement (-30-0 min).

Fig. 3. Graph showing inversion of PPI deficits induced by MK-801 with an initial pulse of 82 dB using comparative compound A.

Fig. 4. Graph showing inhibition of MK-801-induced hyperactivity with compounds in mice.

Detailed description of the invention [0024] The present invention will be described in detail below.

[0025] Unless specifically indicated otherwise, in the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0026] Unless specifically indicated otherwise, in the present specification, the term "may be halogenated" or the term "halogeno" means that one or more (e.g. 1 to 3) halogen atoms may be present as a substituent.

[0027] Unless specifically indicated otherwise, herein, examples of the "C1-10 alkyl" group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.

[0028] Unless specifically indicated otherwise, in the present specification, the "C1-10 alkyl group which may be halogenated" means a C1-10 alkyl group which may be substituted by a halogen atom and examples thereof include trifluoromethyl.

[0029] Unless specifically indicated otherwise, in the present specification, examples of the "C2-6 alkenyl" (group) include vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-buten-1yl, 4-penten-1-yl and 5-hexene-1-yl.

[0030] Examples of the "C2-6 alkynyl (group)" include ethynyl, 1-propin-1-yl, 2-propin-1-yl, 4-pentin-1-yl and 5-hexin-1-yl.

[0031] Unless specifically indicated otherwise, in the present specification, examples of "C3-7 cycloalkyl-C2-6 alkynyl" include cyclopropylethynyl.

[0032] Unless otherwise specifically indicated in the present specification, examples of the "C3-7 cycloalkyl" group "include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0033] Unless specifically indicated otherwise, in this specification, examples of the "C6-14 aryl" group include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl and 2-anthryl.

[0034] Unless otherwise specifically indicated, examples herein of "C7-16 aralkyl" (group) include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 235 naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl , 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl and 4-biphenylmethyl.

[0035] Unless specifically indicated otherwise, in the present specification, examples of "C6-14 aryl-C2-6 alkenyl" (groups) include styryl.

[0036] Unless specifically indicated otherwise, in this specification, "heterocyclic group" (and heterocyclic group in a substituent) means a non-aromatic heterocyclic group or heteroaryl group (i.e., aromatic heterocyclic group) and examples thereof include a 3- to 14-membered heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. This "heterocyclic group" may be monocyclic, bicyclic or tricyclic.

[0037] Examples of the "3- to 14-membered heterocyclic group" include a 3- to 14-membered aromatic heterocyclic group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3 pyrrolyl), furyl (e.g. 2-furyl, 3-furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (e.g. 1 -imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl) (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g. 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxadiazolyl (e.g. 1,2 , 4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl) tetrazolyl pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, indolyl, isoindolyl (e.g. 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (e.g. 1-indolyl, 2-indolyl, 3-indolyl, 4indolyl, 5- indolyl, 6-indolyl, 7-indolyl), benzo [b] furanyl (for example 2-benzo [b] furanyl, 3benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7benzo [b] furanyl), benzo [c] furanyl (for example 1-benzo [c] furanyl, 4-benzo [c] furanyl, 5benzo [c] furanyl), benzo [b] thienyl (for example 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzo [c] thienyl (e.g. 1-benzo [c] thienyl, 4-benzo [c] thienyl, 5-benzo [c] thienyl), indazolyl (e.g. 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (e.g. 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), 1,2-benzisoxazolyl (e.g. 1,2-benzisoxazol-3-yl, 1,236 benzisoxazol-4-yl, 1,2-benzisoxazol- 5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzoxazolyl (e.g. 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl), 1, 2-benzisothiazolyl (e.g., 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,2-benzisothiazol-7-yl), benzothiazolyl (e.g. 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), isoquinolyl (e.g. 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), cininolinyl (e.g. 3-cininolinyl, 4-cininolinyl 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), phthalazinyl (e.g. 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-phthalazinyl), quinazolinyl (e.g. 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (for example 2-chinyl 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl), pyrazolo [1,5-a] pyridyl (for example pyrazolo [1,5-1] pyridin-2-yl, pyrazolo [1,5 -a] pyridin-3-yl, pyrazolo [1,5a] pyridin-4-yl, pyrazolo [1,5-a] pyridin-5-yl, pyrazolo [1,5-a] pyridin-6-yl, pyrazolo [1,5a] pyridin-7-yl), imidazo [1,2-a] pyridyl (e.g. imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyridin-3 -yl, imidazo [1,2-a] pyridin-5-yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridin-7-yl, imidazo [1,2 a] pyridin-8-yl); and a saturated or unsaturated 3 to 14-membered non-aromatic heterocyclic group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as tetrahydrofuryl, oxazolidinyl, imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (e.g. 1-aziridinyl, 2-aziridinyl), azetidinyl (e.g. 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (e.g. 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (e.g. 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl) , piperazinyl (e.g. 1,4-piperazin-1-yl, 1,4-piperazin-2-yl), diazepinyl (e.g. 1,4-diazepin-1-yl, 1,4-diazepin-2-yl, 1,4- diazepin-5-yl, 1,4-diazepin-6-yl), diazocanyl (e.g. 1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1 , 4-diazocan-6-yl, 1,5-diazocan-1-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl), tetrahydropyranyl (e.g. tetrahydropyran-4-yl), morpholinyl (e.g. 4-morpholinyl), thiomorpholinyl (e.g. 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihydropyranyl and dihydrochinolyl.

[0038] Unless otherwise specifically indicated herein, examples of "5- to 10-membered heterocyclic groups" include those having 5- to 10-membered from among the above-mentioned "3- to 14-membered heterocyclic groups".

[0039] Unless otherwise specifically indicated in the present specification, examples of the "aromatic heterocyclic group" (and aromatic heterocyclic moiety in a substituent) include a "3- to 14-membered aromatic heterocyclic group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen "shown above as the aforementioned" heterocyclic group ".

[0040] Unless otherwise specifically indicated herein, examples of the "non-aromatic heterocyclic group" (and aromatic heterocyclic moiety in a substituent) include a "saturated or unsaturated 3- to 14-membered non-aromatic heterocyclic group containing from 1 to 5 heteroatoms selected from a nitrogen atom, sulfur and oxygen "described above as the aforementioned" heterocyclic group ".

[0041] Unless otherwise specifically indicated herein, examples of a "saturated heterocyclic group" (and a saturated heterocyclic group in a substituent) include those saturated from said "non-aromatic heterocyclic group". Specific examples thereof include tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl and piperazinyl.

[0042] Unless otherwise specifically indicated herein, examples of a "5- to 6-membered saturated heterocyclic group" (and a saturated heterocyclic moiety in a substituent) include those having 5- to 6-members of said "saturated heterocyclic groups".

[0043] Unless otherwise specifically indicated herein, examples of the "C1-10 alkoxy" group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0044] Unless otherwise specifically indicated herein, examples of "C3-7 cycloalkyloxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0045] Unless otherwise specifically indicated herein, examples of the "C6-14 aryloxy" group (s) include phenyloxy, 1-naphthyloxy and 2-naphthyloxy.

[0046] Unless otherwise specifically indicated, examples of "C7-16 aralkyloxy" (groups) include benzyloxy and phenethyloxy.

[0047] Unless specifically indicated otherwise, in the present description, examples of "C1-10 alkylcarbonyloxy" (group) include acetoxy and propionyloxy.

[0048] Unless otherwise specifically indicated herein, examples of "C1-10 alkoxycarbonyloxy" include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy and butoxycarbonyloxy.

[0049] Unless otherwise specifically indicated herein, examples of "mono-C 1-10 alkylcarbamoyloxy" (group) include methylcarbamoyloxy and ethylcarbamoyloxy.

[0050] Unless otherwise specifically indicated herein, examples of "diC1-10 alkylcarbamoyloxy" (groups) include dimethylcarbamoyloxy and diethylcarbamoyloxy.

[0051] Unless otherwise specifically indicated, examples herein of "C6-14 arylcarbonyloxy" (groups) include benzoyloxy and naphthylcarbonyloxy.

[0052] Unless otherwise specifically indicated herein, examples of "mono- or di-C6-14 arylcarbamoyloxy" (groups) include phenylcarbamoyloxy and naphthylcarbamoyloxy.

[0053] Unless specifically indicated otherwise, in the present specification, examples of the heterocyclic "heterocyclic (oxy) group" include those similar to said "heterocyclic". Specifically, "examples of the heterocyclic (oxy) group" include a 5- to 14-membered heterocyclic (group) oxy containing 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0054] Unless otherwise specifically indicated herein, examples of the "heterocyclic oxy" aromatic heterocyclic moiety include those similar to the "aromatic heterocyclic group" as examples of said "heterocyclic group". Specifically, examples of the "aromatic heterocyclic (group) oxy" include a 3- to 14-membered aromatic heterocyclic (group) oxo containing 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0055] Unless otherwise specifically indicated herein, examples of "C1-10 alkylsulfonyloxy" (groups) include methylsulfonyloxy and ethylsulfonyloxy.

[0056] Unless specifically indicated otherwise, in the present specification, examples of "C1-10 haloalkylsulfonyloxy" (halo) groups include halogenomethylsulfonyloxy and haloethylsulfonyloxy.

[0057] Unless specifically indicated otherwise, in the present specification, examples of "(C 1-10 alkylsulfanyl) group" include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl and tert-butylsulfanyl.

[0058] Unless otherwise specifically indicated herein, examples of "C3-7 cycloalkylsulfanyl (") include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl and cyclohexylsulfanyl.

[0059] Unless specifically indicated otherwise, herein, examples of the "C6-14 arylsulfanyl (" group) include phenylsulfanyl, 1-naphthylsulfanyl and 2-naphthylsulfanyl. [0060] Unless otherwise specifically indicated, examples herein ( "C7-16 aralkylsulfanyl" groups include benzylsufanyl and phenethylsulfanyl.

[0061] Unless specifically indicated otherwise, in this specification, examples of the "heterocyclic sulfanyl" heterocyclic group include those similar to said "heterocyclic" group. Specifically, examples of the "heterocyclic sulfanyl" group include 5- to 14-membered heterocyclic (sulfanyl) group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0062] Unless specifically indicated otherwise, in the present specification, examples of the "C1-10 alkylcarbonyl" (group) include acetyl, propionyl and pivaloyl.

[0063] Unless otherwise specifically indicated herein, examples of the "C3-7 cycloalkylcarbonyl" (group) include cyclopropylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl.

[0064] Unless otherwise specifically indicated, examples of "C6-14 arylcarbonyl" (group) include benzoyl, 1-naphthyl and 2-naphthyl.

[0065] Unless otherwise specifically indicated, examples of "C7-16 aralkylcarbonyl" (group) include phenylacetyl and 3-phenylpropionyl.

[0066] Unless otherwise specifically indicated herein, examples of the heterocyclic "heterocyclic (carbon) group" include those similar to said "heterocyclic" group. Specifically, examples thereof include a 3 to 14 membered heterocyclic carbonyl (group) containing from 1 up to 5 heteroatoms selected from nitrogen, sulfur and oxygen. In addition, specific examples thereof include picolinoyl, nicotinoyl, isonicotinoyl, 2-tenoyl, 3-tenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl, azetidin-1- ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, azepan-1-ylcarbonyl, azepane 2-ylcarbonyl, azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azokan-1-ylcarbonyl, azokan-2-ylcarbonyl, azokan-3-ylcarbonyl, azokan-4-ylcarbonyl, 1,4-piperazin-1-ylcarbonyl, 1,4-piperazin-2-ylcarbonyl, 1,4-diazepan-1-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl, 1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl, 1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl, 1,4- diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl, 1,5-diazocan-1-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl and 1,5-diazocan-3-ylcarbonyl.

[0067] Unless specifically indicated otherwise, in the present specification, examples of the "(carboxy) group which may be esterified" include carboxy, alkoxycarbonyl which may be substituted, C6-14 aryloxycarbonyl which may be substituted, C7-16 aralkyloxycarbonyl, which may be substituted, silyloxycarbonyl which may be substituted (for example TMS-O-CO-, TES-O-CO-, TBS-O-CO-, TIPS-O-CO-, TBDPSO-CO-) [0068] Unless otherwise specifically indicated in this description, examples of the "C1-10 alkoxycarbonyl" (group) include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

[0069] Unless specifically indicated otherwise, herein, examples of "C6-14 aryloxycarbonyl (group)" include phenoxycarbonyl.

[0070] Unless specifically indicated otherwise, in the present specification, examples of "C7-16 aralkylcarbonyl" (group) include benzyloxycarbonyl and phenethyloxycarbonyl.

[0071] Unless specifically indicated otherwise, in the present specification, examples of "C1-10 alkylsulfonyl (group)" include methylsulfonyl and ethylsulfonyl.

[0072] Unless otherwise specifically indicated herein, examples of "C3-7 cycloalkylsulfonyl" group include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl.

[0073] Unless specifically indicated otherwise, in the present specification, examples of the "C6-14 arylsulfonyl (group)" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl. [0074] Examples of the heterocyclic moiety not specifically indicated herein "Heterocyclic (sulfonyl) group" includes those similar to said "heterocyclic group". Specifically, examples of the "heterocyclic (sulfonyl) group" include a 5- to 14-membered heterocyclic (sulfonyl) group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0075] Unless specifically indicated otherwise, in this specification, examples of the saturated heterocyclic "saturated heterocyclic (sulfonyl) group" include those similar to said "heterocyclic" group. Specifically, examples of the "heterocyclic (sulfonyl) group" include 5- to 14 - a heterocyclic sulfonyl (group) containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0076] Unless specifically indicated otherwise, herein, examples of "C1-10 alkylsulfinyl (group)" include methylsulfinyl and ethylsulfinyl.

[0077] Unless specifically indicated otherwise, in the present specification, examples of "C3-7 cycloalkylsulfinyl" include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsufinyl and cyclohexylsulfinyl.

[0078] Unless specifically indicated otherwise, in the present specification, examples of the "C6-14 arylsulfinyl (group)" include phenylsulfinyl, 1-naphthylsulfinyl and 2-naphthylsulfinyl. [0079] Examples of the heterocyclic moiety not specifically indicated herein "Heterocyclic (sulfinyl) group" includes those similar to said "heterocyclic group". Specifically, examples of the "heterocyclic (sulfinyl) group" include a 5- to 14-membered heterocyclic (sulfinyl) group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

[0080] Unless otherwise specifically indicated herein, examples of "C1-10 alkylcarbamoyl (group)" include methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl.

[0081] Unless otherwise specifically indicated, examples of "mono- or di-C 1-10 alkylamino" (group) include methylamino, ethylamino, propylamino, dimethylamino and diethylamino.

[0082] Unless otherwise specifically indicated herein, examples of "C1-10 alkylcarbonylamino (group)" include acetylamino, propionylamino and pivaloylamino.

[0083] Unless otherwise specifically indicated herein, examples of the "heterocyclic amino" heterocyclic moiety include those similar to said "heterocyclic". Examples of the "heterocyclic amino" group include 2-pyridylamino.

[0084] Unless otherwise specifically indicated herein, examples of the "heterocyclic carbonyl moiety" of "heterocyclic carbonylamino (group)" include those similar to said "heterocyclic carbonyl group". Examples of the "heterocyclic carbonylamino group" include pyridylcarbonylamino.

[0085] Unless otherwise specifically indicated in the present specification, examples of the "heterocyclic (oxy) carbonocyclic (heterocyclic) group" include those similar to said "heterocyclic group". Examples of the "heterocyclic oxycarbonylamino (group)" include 2-pyridyloxycarbonylamino.

[0086] Unless specifically indicated otherwise, in the present specification, examples of the "heterocyclic" (heterocyclic) sulfonylamino (group) include those similar to said "heterocyclic group". Examples of the "heterocyclic sulfonylamino (group)" include 2-pyridylsulfonylamino.

[0087] Unless otherwise specifically indicated, examples herein of "C1-10 alkoxycarbonylamino (group)" include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino and butoxycarbonylamino.

[0088] Unless specifically indicated otherwise, in the present specification, examples of the "C1-10 alkylsulfonylamino (group)" include methylsulfonylamino and ethylsulfonylamino. [0089] Unless specifically indicated otherwise, in the present description, the examples of "(mono) or di" (groups) "C3-7 cycloalkylamino" include cyclopropylamino, cyclopentylamino and cyclohexylamino.

[0090] Unless otherwise specifically indicated herein, examples of "C3-7 cycloalkylcarbonylamino" include cyclopropylcarbonylamino, cyclopentylcarbonylamino and cyclohexylcarbonylamino.

[0091] Unless otherwise specifically indicated herein, examples of "C3-7 cycloalkyloxycarbonylamino" include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino and cyclohexyloxycarbonylamino.

[0092] Unless specifically indicated otherwise, in the present specification, examples of "C3-7 cycloalkylsulfonylamino" include cyclopropylsulfonylamino, cyclopentylsulfonylamino and cyclohexylsulfonylamino.

[0093] Unless otherwise specifically indicated, examples of "mono- or di-C6-14 arylamino (group)" include phenylamino and diphenylamino.

[0094] Unless specifically indicated otherwise, in the present specification, examples of "mono- or di-C7-16 aralkylamino (group)" include benzylamino.

[0095] Unless otherwise specifically indicated, examples of "C6-14 arylcarbonylamino" (groups) include benzoylamino and naphthylamino.

[0096] Unless otherwise specifically indicated herein, examples of "C6-14 arylsulfonylamino (group)" include phenylsulfonylamino, 2-naphthylsulfonylamino and 1-naphthylsulfonylamino.

[0097] The symbols in the above-mentioned formulas (formula (Io) and formula (I)) will be explained below.

[0098] In the above-mentioned formula, R¹ is a substituent selected from the group A substituents described below.

[Group A substituents] [0099] (1) a halogen atom;

(2) nitro group;

(3) cyano group;

(4) a carboxy group that can be esterified;

(5) C1-10 alkyl which may be substituted;

(6) a C2-6 alkenyl group which may be substituted;

(7) a C2-6 alkynyl group which may be substituted (for example a C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted;

(8) a C3-7 cycloalkyl group which may be substituted;

(9) C6-14 aryl which may be substituted;

(10) a C7-16 aralkyl group which may be substituted;

(11) C6-14 aryl-C2-6 alkenyl which may be substituted;

(12) heterocyclic group which may be substituted;

(13) hydroxyl group;

(14) a C1-10 alkoxy group which may be substituted;

(15) a C3-7 cycloalkyloxy group which may be substituted;

(16) C6-14 aryloxy which may be substituted;

(17) a C7-16 aralkyloxy group which may be substituted;

(18) a C1-10 alkylcarbonyloxy group which may be substituted;

(19) a C1-10 alkoxycarbonyloxy group which may be substituted;

(20) mono-C 1-10 alkylcarbamoyloxy group which may be substituted;

(21) di-C 1-10 alkylcarbamoyloxy which may be substituted;

(22) C6-14 arylcarbonyloxy group which may be substituted;

(23) mono- or di-C6-14 arylcarbamoyloxy which may be substituted;

(24) heterocyclic oxy group which may be substituted (e.g. aromatic heterocyclic oxy group which may be substituted) (25) C1-10 alkylsulfonyloxy group which may be substituted (e.g. (halogen) group C1-10 alkylsulfonyloxy which can be substituted);

(26) mercapton group;

(27) C1-10 alkylsulfanyl which may be substituted;

(28) a C3-7 cycloalkylsulfanyl group which may be substituted;

(29) C6-14 arylsulfanyl which may be substituted;

(30) a C7-16 aralkylsulfanyl group which may be substituted;

(31) heterocyclic sulfanyl group which may be substituted;

(32) formyl group;

(33) a C1-10 alkylcarbonyl group which may be substituted;

(34) a C3-7 cycloalkylcarbonyl group which may be substituted;

(35) C6-14 arylcarbonyl group which may be substituted;

(36) a C7-16 aralkylcarbonyl group which may be substituted;

(37) heterocyclic carbonyl group which may be substituted;

(38) a C 1-10 alkylsulfonyl group which may be substituted;

(39) a C3-7 cycloalkylsulfonyl group which may be substituted;

(40) C6-14 arylsulfonyl which may be substituted;

(41) heterocyclic sulfonyl group which may be substituted;

(42) a C 1-10 alkylsulfinyl group which may be substituted;

(43) a C3-7 cycloalkylsulfinyl group which may be substituted;

(44) C6-14 arylsulfinyl which may be substituted;

(45) heterocyclic sulfinyl group which may be substituted;

(46) sulfone group;

(47) sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) thiocarbamoyl group:

(51) carbamoyl group which may be substituted [for example alkylcarbamoyl group which may be substituted] (52) amino group, mono- or di-C1-10 alkylamino group which may be substituted, mono-or di-C3 group -7 cycloalkylamino which may be substituted, mono- or di-C6-14 arylamino which may be substituted, mono- or di-C7-16 aralkylamino which may be substituted, heterocyclic amino which may be substituted, C6-14 arylcarbonylamino group which may be substituted, formylamino group, C1-10 alkylcarbonylamino group which may be substituted (e.g. mono- (C1-10 alkylcarbonyl) amino group which may be substituted), C3-7 cycloalkylcarbonylamino group, which may be substituted, a heterocyclic carbonylamino group which may be substituted, a C3-7 cycloalkyloxycarbonylamino group which may be substituted, a heterocyclic oxycarbonylamino group, which may be substituted, a carbamoylamino group which may be substituted, a C1-10 alkylsulfonylamino group which may be substituted, a C3-7 cycloalkylsulfonylamino group which may be substituted, a heterocyclic sulfonylamino group which may be substituted, a C6-14 arylsulfonylamino group, which can be substituted] [0100] Among the above-mentioned group A substituents, "C1-10 alkoxycarbonyl group which may be substituted", "C1-10 alkyl group, which may be substituted "," a C2-6 alkenyl group which may be substituted "," a C2-6 alkynyl group which may be substituted "," a C1-10 alkoxy group which may be substituted "," a C1-10 group alkylcarbonyloxy which may be substituted "," C1-10 alkoxycarbonyloxy group which may be substituted "," mono-C1-10 alkylcarbamoyloxy group which may be substituted "," di and C1-10 alkylcarbamoyloxy group which may be substituted ", "C1-10 alkylsulfanyl, which may be substituted "," C1-10 alkylcarbonyl group which may be substituted "," C1-10 alkylsulfonyl group which may be substituted "," C1-10 alkylsulfinyl group which may be substituted "," C1-10 group alkylcarbamoyl which may be substituted, "" mono- or di-C 1-10 alkylamino which may be substituted, "" C 1-10 alkylcarbonylamino which may be substituted, "" mono- (C 1-10 alkylcarbonyl) amino which can be substituted "

"C1-10 alkoxycarbonylamino which may be substituted" and "C1-10 alkylsulfonylamino which may be substituted" whose substituents may be selected from the following group B substituents. The number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 and additionally preferably is 1.

[Group B substituents] [0101] Group B substituents consist of:

(a) a halogen atom;

(b) a hydroxyl group;

(c) nitro;

(d) a cyano group;

(e) a C6-14 aryl group which may be substituted (a "C6-14 aryl group" may be substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, C1-10 alkyl which may be halogenated , mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono- or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3- 7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C 1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C 1-10 alkylsulfanyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1-10 alkylcarbonyl and - or di-C6-14 arylcarbamoyl);

(f) a C6-14 aryloxy group that may be substituted (a "C6-14 aryloxy group" may be substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, C1-10 alkyl which may be halogenated , mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono- or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3- 7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-di- -10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl);

(g) a C7-16 aralkyloxy group which may be substituted (a "C7-16 aralkyloxy group" may be substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino, C1-10 alkyl which may be halogenated , mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono- or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3- 7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-di- -10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl);

(h) a mono- or di-5- to 10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (e.g. furyl, pyridyl, thienyl, pyrrolidine, 1-piperidinyl, 4-piperidinyl, piperazinyl , 1-morpholinyl, 4-thiomorpholinyl, azepan-1-yl, azokan-1-yl, azonan-1-yl, 3,4-dihydroisoquinolin-2-yl) which can be substituted ("mono- or di-5 - to a 10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen atom, sulfur and oxygen "may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C1-10 alkyl which may be halogenated, mono- or di-C1-10 alkylamino, mono- or di-C6 -14 arylamino, mono- or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl . C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl);

(i) an amino group which may be substituted [for example an amino group which may be substituted by one or two substituents selected from the group consisting of a C1-10 alkyl, C2-6 alkenyl, C6-14 aryl, C7-16 group aralkyl, heterocyclic and heterocyclic-alkyl (C1-10 alkyl, C2-6 alkenyl, C6-14 aryl, C7-16 aralkyl, heterocyclic and heterocyclic-alkyl may be substituted by halogen, hydroxyl, cyano, amino, C1-10 alkyl, which may be halogenated (non-alkyl and alkenyl substituents), mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono- or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C3-7 cycloalkyloxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxy -10 alkylsulfanyl, C3-7 cycloalkylsulfanyl, C1-10 alkylsulfinyl, C3-7 cycloalkylsulfinyl, C1-10 alkylsulfonyl, C3-7 cycloalkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl, mono- or di-C6-14 arylcarbamoyl. "Heterocyclic" and "heterocyclic" in the "heterocyclic-alkyl" are the same as the above-mentioned "heterocyclic";

(j) a C3-7 cycloalkyl group;

(k) a C 1-10 alkoxy group that may be substituted (a "C 1-10 alkoxy group" may be substituted by one or more substituents selected from halogen, hydroxy, amino, mono- or di-C 1-10 alkylamino, mono - or di-C6-14 arylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl);

(1) formyl group;

(m) a C 1-10 alkylcarbonyl group (e.g. acetyl);

(n) a C 3-7 cycloalkylcarbonyl group;

(o) C6-14 arylcarbonyl group;

(p) groups C7- ₁₆ aralkylcarbonyl;

(q) a C1-10 alkoxycarbonyl group;

(r) C6-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl group;

(t) a C1-10 alkylsulfanyl group;

(u) a C 1-10 alkylsulfinyl group;

(v) a C 1-10 alkylsulfonyl group;

(w) carbamoyl group;

(x) thiocarbamoyl group;

(y) mono-C 1-10 alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl);

(z) di-C 1-10 alkylcarbamoyl group (e.g. dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl);

(aa) a mono- or di-C6-14 arylcarbamoyl group (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl); and (bb) a mono- or di-5- to 7-membered heterocyclic carbamoyl group containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (e.g. 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl) ).

[0102] Among the above-mentioned group A substituents, "C6-14 aryloxycarbonyl group which may be substituted", "C7-16 aralkyloxycarbonyl group which may be substituted", "C3-7 cycloalkyl-C2-6 alkynyl group which may be substituted "," a C3-7 cycloalkyl group which may be substituted "," a C6-14 aryl group which may be substituted "," a C7-16 aralkyl group which may be substituted "," a C6-14 aryl group C2-6 alkenyl which may be substituted ", "Heterocyclic group which may be substituted", "C3-7 cycloalkyloxy group which may be substituted", "C6-14 aryloxy group which may be substituted", "C7-16 aralkyloxy group which may be substituted", " C6-14 arylcarbonyloxy group which may be substituted "," mono- or di-C6-14 arylcarbamoyloxy group which may be substituted "," heterocyclic oxy group which may be substituted "," aromatic heterocyclic oxy group which may be substituted " "C3-7 cycloalkylsulfanyl group which may be substituted", "C6-14 arylsulfanyl group which may be substituted", "C7-16 aralkylsulfanyl group which may be substituted", "heterocyclic sulfanyl group which may be substituted", "C3-7 cycloalkylcarbonyl group which may be substituted", "C6-14 arylcarbonyl group which may be substituted", "C7-16 aralkylcarbonyl group which may be substituted", "heterocyclic carbonyl group, which may be substituted "," a C3-7 cycloalkylsulfonyl group which may be substituted "," a C6-14 arylsulfonyl group which may be substituted "," a heterocyclic sulfonyl group which may be substituted "," a C3-7 cycloalkylsulfinyl group, which may be substituted "," C6-14 arylsulfinyl group which may be substituted "," heterocyclic sulfinyl group which may be substituted "," carbamoyl group which may be substituted "," amino group, which may be substituted "," mono or di-C3-7 cycloalkylamino group which may be substituted, "mono or di-C6-14 arylamino group which may be substituted," mono or di-C7-16 group aralkylamino which may be substituted, "a heterocyclic amino group which may be substituted," a C6-14 arylcarbonylamino group which may be substituted, "a C3-7 cycloalkylcarbonylamino group which may be substituted," a heterocyclic carbonylamino group, which may be substituted, "a C3-7 cycloalkyloxycarbonylamino group which may be substituted," a heterocyclic oxycarbonylamino group which may be substituted, "a carbamoylamino group which may be substituted," an alkylsulfonylamino group which may be substituted, "the C3-7 group cycloalkylsulfonylamino which may be substituted, "a heterocyclic sulfonylamino group which may be substituted and" a C6-14 arylsulfonylamino group which may be substituted, whose substituents may be selected from the above-mentioned group of B substituents and the following group of B 'substituents. The number of substituents being in the range of from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents, and in addition is preferably 1 substituent.

[Group B 'substituents] [0103] Group B' substituents consists of:

(a) a C1-10 alkyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino group , mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl;

(b) a C2-6 alkenyl group which may be substituted by one or more substituents selected from a halogen atom, a hydroxyl, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino group , mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl . C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl; and (c) a C2-6 alkynyl group which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-14 arylamino, mono or di-C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C6-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl.

[0104] Of these, R¹ preferably is, for example, a C 1-10 alkyl group which may be substituted, a C 3-7 cycloalkyl group which may be substituted, a C 6-14 aryl group which may be substituted, a non-aromatic heterocyclic group which may be substituted or a heterocyclic group which can be substituted.

[0105] Of these, specifically, R¹ is, for example, preferably a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group which may be substituted, a C1-10 alkoxy group which may be substituted, more preferably a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group and a C1-10 alkoxy group, and additionally preferably a phenyl group, which can be substituted by 1 to 5 halogen atoms.

[0106] In another aspect of the present invention as R¹, in particular, for example:

A 5- or 6-membered aromatic group (preferably a phenyl group, a pyridyl group) which can be substituted by one or more substituents selected from a halogen atom (preferably a chlorine atom, fluorine atom), cyano group, hydroxyl group, C1-10 group alkyl (preferably methyl, isobutyl) which may be substituted, C1-10 alkoxy (preferably methoxy) which may be substituted, C1-10 alkylsulfanyl, which may be substituted, a C1-10 alkylsulfinyl group which may be substituted, a C1-10 alkylsulfonyl group which may be substituted and an amino group which may be substituted.

[0107] Wherein the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents, and in addition is preferably 1 substituent.

[0108] In particular, as R¹ for example a C6-14 aryl group which may be substituted and a heteroaryl group which may be substituted are desired.

[0109] R¹ is preferably, for example, preferably a phenyl group which is substituted by one or more (preferably from 1 to 5) substituents selected from (a) a C1-10 alkyl group (e.g. isopropyl, isobutyl) and (b) halogen atoms (e.g. chlorine) , fluorine), C1-10 alkyl (e.g. methyl), C1-10 alkoxy (e.g. methoxy).

[0110] In the above-mentioned formula, R² is a substituent selected from the above-mentioned group A substituents.

[0111] Of these, R² is preferably, for example, preferably a halogen atom, a hydroxyl group, a C 1-10 alkyl group which may be substituted, or a C 1-10 alkoxy group which may be substituted, more preferably a C 1-10 alkoxy group which may be substituted by one or more substituents selected from a halogen atom, a C 1-10 alkoxy group and a C 3-7 cycloalkyl group and additionally preferably a C 1-10 alkoxy group.

[0112] In another aspect of the present invention as R², in particular, for example, (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a C1-10 alkyl group which may be substituted by one or more substituents selected from halogen atoms, hydroxyl group, amino group and C1-10 alkoxy group, (v) amino group which may be mono- or di-substituted with a C1-10 alkyl group or (vi) C1-10 alkoxy group, which may be substituted by one or more substituents selected from the cyano group, amino group, C1-10 alkoxy group, hydroxyl group, halogen atoms and C3-7 cycloalkyl group, and more preferably, for example, (i) a hydrogen atom, (ii ) hydroxyl group, (iii) C1-10 alkyl group (e.g. methyl) or (iv) C1-10 alkoxy group (e.g. methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, difluoromethoxy), which may be substituted by one or more substituents selected from halogen atoms and a C3-7 cycloalkyl group.

β [0113] In the above-mentioned formula, R³ represents a hydrogen atom or a substituent selected from the above-mentioned group A substituents.

β [0114] Of these, R³ preferably it is, for example, a halogen atom, a hydroxyl group, a C1-10 alkyl group which may be substituted or a C1-10 alkoxy group which may be substituted.

β [0115] Of these, specifically, R³ preferably it is, for example, a hydrogen atom or a C 1-10 alkoxy group which may be substituted, more preferably a hydrogen atom or a C 1-10 alkoxy group and additionally preferably a hydrogen atom.

β [0116] In another aspect of the present invention as R³, in particular, for example (i) a hydrogen atom, (ii) halogen atoms, (iii) a C1-10 alkyl group which may be substituted by one or more substituents selected from halogen atoms, hydroxyl group, amino group and C1-10 alkoxy, (iv) amino which may be mono- or di-substituted with C1-10 alkyl or (vi) C1-10 alkoxy, with hydrogen and C1-10 alkyl being more preferred (for example methyl).

[0117] In the above-mentioned formula, ring A is an aromatic ring which may be substituted.

[0118] The "aromatic ring" of the "aromatic ring which may be substituted" is preferably a 5 to 16-membered aromatic ring, more preferably a 5 to 6-membered aromatic ring and additionally preferably a 6-membered aromatic ring.

[0119] The "aromatic ring" of the "aromatic ring which may be substituted" represented by ring A includes, for example (i) an aromatic cyclic hydrocarbon, (ii) an aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur .

[0120] Said "(i) aromatic cyclic hydrocarbon includes, for example, aromatic cyclic C6-14 hydrocarbons such as benzene, naphthalene, anthracene, phenanthrene, acenaphthylene (preferably aromatic cyclic C6-12 hydrocarbons, benzene is particularly preferred).

[0121] Said "(ii) aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur includes, for example, 5- or 6-membered aromatic heterocyclic monocyclic rings such as furan, thiophene, pyrrole, 1, 3-oxazole, isoxazole, 1,3-thiazole, isothiazole, imidazole, pyrazole, 1,2,3oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3,4-tetrazine, 1,2,3,5- tetrazine, 1,2,4,5-tetrazine; and 8 to 16-membered (preferably 8 to 12-membered) aromatic fused heterocyclic rings (preferably heterocyclic rings formed by condensation of 1 to 2 of said 5- to 6-membered aromatic monocyclic heterocyclic rings (preferably 1 ring) with 1 to 2 benzene rings (preferably 1 ring) or heterocyclic rings formed by condensation of 2 to 3 of said identical 5- to 6-membered aromatic monocyclic heterocyclic rings or various heterocyclic rings) such as benzofuran, isobenzofuran, benzothiophene, indole, isoindole, 1Hindazole, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, 1Hbenzotriazole, quinoline, isoquinoline, cinnoline, quinoline, pteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, fenoxatin, tiantren, phenanthridine, phenanthroline, indolizine, pyrrolopyridine, pyrrolo [1,2-b] pyridazine, 1H-pyrrolo [2,3-b] pyrazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2- b] pyridazine, imidazo [1,2a] pyrimidine, 1,2,4-triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-b] pyridazine).

[0122] When "(ii) an aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur contains a nitrogen atom, the aromatic heterocyclic ring may form an N-oxide.

[0123] Of these, benzene, pyridine, pyridazine, pyrimidine, pyrazine, pyridine N-oxide, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2 , 3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, isothiazole, 1,3oxazole, 1,3-thiazole, 1 , 2,3-triazole, 1,2,4-triazole, tetrazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, naphthalene, quinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole , indole, 1H-indazole, 1H-pyrrolo [2,3-b] pyrazine, 1H-pyrrolopyridine, 1H-imidazopyridine, 1H-imidazopyrazine, triazine, isoquinoline, benzothiadiazole, benzisoxazole, benzisothiazole, indazol, purine, isoquinoline, phthalazine, phthalazine the like, in particular benzene or pyridine is preferred, and benzene is most preferred.

[0124] The substituents of the "aromatic ring that can be substituted" represented by ring A include, for example, substituents selected from the above-mentioned group A substituents.

In particular, preferred examples of the "aromatic ring which may be substituted" substituents include (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted, (3) a C1-10 alkoxy group which may be substituted, (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms that can be substituted, (5) a C1-10 alkylsulfonyl group that can be substituted, (6) C3-7 cycloalkyl group, which may be substituted, (7) cyano, (8) carbamoyl, which may be substituted, (9) C1-10 alkylsulfonyloxy, which may be substituted, (10) C3-7 cycloalkyl-C2-6 alkynyl, which may be substituted, (11) tetrahydropyranyl, which may be substituted, (12) dihydropyranyl, which may be substituted, (13) a mono- (C1-10 alkylcarbonyl) amino group, which may be substituted, (14) C1-10 alkoxycarbonyl, which may be substituted, (15) a C1-10 alkylsulfinyl group which may be substituted, (16) a C1-10 alkylsulfanyl group which may be substituted.

[0126] As is apparent to those skilled in the art, a "4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as" "4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms that can be substituted "is contained in a" heterocyclic group "of a" heterocyclic group that can be substituted ".

[0127] The number of substituents is preferably in the range of 1 to 5.

[0128] The number of substituents of the "heterocyclic group which may be substituted" is one or more, preferably in the range of 1 to 5, more preferably in the range of 1 to 3, additionally preferably one or two.

[0129] When the number of substituents is two or more, the substituents on ring A can be combined to form a ring that can be substituted. A "ring" "which can be substituted" includes a 5- to 6-membered heterocyclic ring containing one nitrogen atom or two oxygen atoms as heteroatoms.

[0130] A "ring" may be substituted by one or more (preferably 1 to 5) substituents selected from the group A substituents.

[0131] In another aspect of the present invention, preferred examples of the "aromatic ring which may be substituted" substituents represented by ring A include halogen atoms (preferably halogen), cyano, hydroxyl, C1-10 alkyl, which may be substituted (preferably a C 1-10 alkyl group which may be substituted by 1 to 3 halogen atoms [e.g. a trifluoromethyl group]), a C 1-10 alkoxy group, which may be substituted (preferably a C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms [e.g. a methoxy group, a difluoromethoxy group]), a carbamoyl group, a heterocyclic oxy group (preferably a 5- to 10-membered heterocyclic oxy group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur [e.g. a benzimidazolyloxy group]), a C1-10 alkylsulfanyl group which may be substituted, a C1-10 alkylsulfinyl group, which may be substituted, a C 1-10 alkylsulfonyl group which may be substituted (preferably a C 1-10 alkylsulfonyl group [e.g., a methylsulfonyl group]), a heterocyclic sulfonyl group (preferably

5- to 6-membered saturated heterocyclic sulfonyl group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur [e.g. a morpholinylsulfonyl group]), an amino group which may be substituted, a C3-7 cycloalkyl group (preferably a C3-7 group Cycloalkyl [e.g. cyclohexyl group]) and a saturated heterocyclic group (preferably a 5- to 6-membered saturated heterocyclic group containing from 1 to 3 heteroatoms selected from a nitrogen atom, oxygen and sulfur [for example, a morpholinyl group and a piperidyl group]).

[0132] Ring A is preferably, for example, a benzene ring which can be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group that can be substituted, (3) a C1-10 group alkoxy which may be substituted, (4) a C3-7 cycloalkyl group, (5) a halogen-C1-10 alkylsulfonyloxy group, (6) C3-7 cycloalkyl-C2-6 alkynyl group and (7) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by one or more the number of substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that can be substituted, and a C 1-10 alkyl group that can be substituted.

[0133] Ring A is more preferably, for example, a benzene ring, which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group, which may be substituted by 1 to 3 halogen atoms, ( 3) a C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms, (4) a C3-7 cycloalkyl group, (5) a C1-10 alkylsulfonyloxy halo group, (6) C3-7 cycloalkyl-C2-6 alkynyl group and (7) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that can be substituted by a halogen atom, and a C 1-10 alkyl group that can be substituted by a halogen atom.

[0134] Ring A is additionally preferably, for example, a benzene ring which is substituted by (1) (i) 1 or 2 halogen atoms or (ii) one C1-10 alkoxy group and (2) one 4- to 6-membered group heterocyclic containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C1-10 alkoxycarbonyl group, a C1-10 alkoxy group, which may be substituted by a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom.

[0135] Here, as "one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms", for example, a morpholine group, pyrrolyl group, dihydropyrrolyl group, pyrazolyl group, dihydropyrazolyl group, piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group or imidazolidinyl group.

[0136] In another aspect of the present invention, as ring A, in particular, for example, a 5- to 6-membered aromatic group is preferred, which may be substituted by one or more substituents selected from halogen, cyano, hydroxyl, groups C1-10 alkyl which may be substituted, C1-10 alkoxy which may be substituted, carbamoyl group, C1-10 alkylsulfanyl group which may be substituted, a C 1-10 alkylsulfinyl group that can be substituted, a C 1-10 alkylsulfonyl group that can be substituted, a heterocyclic sulfonyl group, an amino group that can be substituted, a C 3-7 cycloalkyl group and a saturated heterocyclic group and more particularly, 5- up to a 6-membered aromatic group (e.g. phenyl, pyridyl) which may be substituted by one or more substituents selected from (a) a halogen atom (e.g. chlorine, fluorine), (b) a cyano group, (c) a C1-10 alkyl group which may be substituted by 1 to 3 halogen atoms (e.g. methyl, trifluoromethyl), (d) a C3-7 cycloalkyl group (e.g. methyl, trifluoromethyl), ( e) a C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g. difluoromethoxy, methoxy), (f) a 5- to 10-membered heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. morpholinyl, benzimidazolyl, piperidinyl), (g) a C1-10 alkylsulfonyl group (e.g. methylsulfonyl), (h) a 5- to 10-membered heterocyclic sulfonyl group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. morpholinylsulfonyl) and (i) a carbamoyl group.

[0137] In the above-mentioned formula, ring B is a "5-membered heterocyclic aromatic ring that can be substituted" (also referred to as a 5-membered heteroaromatic ring that can be substituted).

[0138] Examples of the "5-membered aromatic heterocyclic ring that can be substituted" represented by ring B include 5-membered aromatic heterocyclic rings containing from 1 to 4 heteroatoms (preferably 1 to 2 atoms) selected from nitrogen, oxygen and sulfur, such as pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, isothiazole, 1,3-oxazole, 1,3-thiazole, triazole (e.g. 1,2,3-triazole, 1,2,4-triazole), tetrazole . oxadiazole (e.g. 1,2,3-oxadiazole) and thiadiazole (e.g. 1,2,3-thiadiazole). Of these, pyrazole, triazole and tetrazole are preferred, and pyrazole is most preferred.

[0139] As substituents of the "5-membered aromatic heterocyclic ring represented by ring B, there may be mentioned, for example, substituents selected from the above-mentioned group A substituents.

[0140] Preferable examples of substituents include a halogen atom, a C 1-10 alkyl group that can be substituted, and a C 6-14 aryl group that can be substituted, more preferred examples include a halogen atom, a C 1-10 alkyl group, and a C 6-14 aryl group, further preferred examples include a C 1-10 alkyl group (e.g., methyl).

[0141] Also preferably, ring B does not have such a substituent. In other words, ring B has only the substituents shown in general formula (I0).

[0142] Ring B is preferably a 5-membered nitrogen-containing aromatic heterocyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which can be substituted by a C1-10 alkyl group (e.g. a methyl group) (e.g. pyrazole, triazole, tetrazole).

[0143] As ring B, an imidazole ring, a pyrazole ring, a triazole ring or a tetrazole ring is preferred, each of which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by halogen atom, more preferably is a pyrazole ring which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group, which may be substituted by a halogen atom, a pyrazole ring is particularly preferred.

[0144] In another aspect of the present invention, ring B is preferably a 5-membered nitrogen-containing aromatic heterocyclic ring containing from 1 to 3 nitrogen atoms (e.g. pyrazole, triazole, tetrazole) which may be substituted by a C1-10 alkyl group (e.g. methyl group).

[0145] Additionally, preferably, examples of the substituents, moieties and rings explained herein are used in combination.

For example, the following compounds i.e. compounds (I0-A), (I0-B), (I0-C), (I0-D), (I0-E), (I0-F) and (I0-F) G) are preferred as compound (IO).

[Compound (I0-A)] [0147] The above-described compound (I0) in which

R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group which may be substituted and a C1-10 alkoxy group which may be substituted,

R² is a halogen atom, a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted,

R³ is a hydrogen atom or a C 1-10 alkoxy group which may be substituted, ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-10 alkyl group which may be substituted, (3) C1-10 alkoxy group which may be substituted, (4) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted, (5) C1-10 alkylsulfonyl which may be substituted, (6) C3-7 cycloalkyl which may be substituted, (7) cyano, (8) carbamoyl which may be substituted, (9) C1 -10 alkylsulfonyloxy which may be substituted, (10) C3-7 cycloalkyl-C2-6 alkynyl which may be substituted, (11) tetrahydropyranyl which may be substituted, (12) dihydropyranyl which may be substituted, (13) mono- (C1-10 alkylcarbonyl) amino which may be substituted, (14) C1-10 alkoxycarbonyl which may be substituted, (15) C1-10 alkylsulfinyl which may be substituted and (16) a C1-10 alkylsulfanyl group which may be substituted and the B ring is an imidazole ring, a pyrazole ring, a triazole ring or a tetrazole ring, each of which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom, wherein optional substituents are as described above.

[Compound (I0-B)] [0148] The above-described compound (I0-A), wherein ring A is a benzene ring which can be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) group C1 -10 alkyl which may be substituted, (3) a C1-10 alkoxy group which may be substituted, (4) a C3-7 cycloalkyl group, (5) a C1-10 alkylsulfonyloxy halo group, (6) C3-7 cycloalkyl-C2-6 alkynyl group and (7) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by one or more substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that can be substituted, and a C 1-10 alkyl group that can be substituted, wherein optional substituents are as described above.

[Compound (I0-C)] [0149] The above-described compound (I0) in which

R¹ is a phenyl group which may be substituted by 1 to 5 substituents selected from a halogen atom, a C1-10 alkyl group and a C1-10 alkoxy group,

R² is a C1-10 alkoxy group which may be substituted by one or more substituents selected from a halogen atom, a C1-10 alkoxy group and a C3-7 cycloalkyl group,

R³ is a hydrogen atom or a C1-10 alkoxy group, ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group which may be substituted by 1 to 3 halogen atoms, (3) C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms, (4) C3-7 cycloalkyl group, (5) halogen C1-10 alkylsulfonyloxy group, (6) C3-7 cycloalkyl-C2-6 alkynyl group and (7) 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C 1-10 alkoxycarbonyl group, a C 1-10 alkoxy group that can be substituted by a halogen atom, and a C 1-10 alkyl group that can be substituted by a halogen atom, ring B is a pyrazole ring which may be further substituted with from 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by a halogen atom.

[Compound (I0-D)] [0150] The above-described compound (I0) in which

R¹ is a phenyl group which may be substituted by 1 to 5 halogen atoms,

R² is a C1-10 alkoxy group, β

R³ is hydrogen, ring A is a benzene ring which is substituted with (1) (i) 1 or 2 halogen atoms or (ii) one C1-10 alkoxy group and (2) one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, an oxo group, a C1-10 alkoxycarbonyl group, a C1-10 alkoxy group, which can be substituted by a halogen atom and a C1-10 alkyl group that can be substituted by a halogen atom, ring B is a pyrazole ring.

[0151] Here, as "one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms as heteroatoms", for example, a morpholine group, pyrrolyl group, dihydropyrrolyl group, pyrazolyl group, dihydropyrazolyl group is preferred , piperidyl, azetidinyl, pyrrolidinyl, oxazolidinyl, imidazolyl or imidazolidinyl.

[Compound (I0-E)] [0152] The above-described compound (I0) in which

R¹ is an aromatic group which is within the definition of the substituents of the group A of the substituents described above and which may be substituted, ring A is an aromatic ring which is substituted by (a) one substituent selected from (1) a C3-7 cycloalkyl group which may be substituted and (2) a 4- to 6-membered heterocyclic group containing from 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted and (b) one or more additional substituents, wherein optional substituents are as described above.

[0153] Here, particularly preferably, the additional substituents are from 1 to 4 substituents selected from (1) a halogen atom, (2) an oxo group, (3) a hydroxyl group, (4) a C1-10 alkyl group which may be substituted, (5) C1-10 alkoxy group which may be substituted, (6) C1-10 alkylsulfonyl group, (7) morpholin-4-ylsulfonyl group, (8) cyano group, (9) carbamoyl group, (10) halogeno group C1-10 alkylsulfonyloxy, (11) C3-7 cycloalkyl-C2-6 alkynyl groups, (12) di-C 1-10 alkylamino group, (13) mono- (C 1-10 alkylcarbonyl) amino group, (14) C 1-10 alkoxycarbonyl group, (15) phenoxy group, (16) C 1-10 alkylsulfinyl group, ( 17) benzimidazol-2-yloxy and (18) benzimidazol-2-ylsulfonyl.

[Compound (I0-F)] [0154] The above-described compound (I0-E) in which

R¹ is a phenyl group which may be substituted

R² is a halogen atom, a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted,

R³ is a hydrogen atom or a C 1-10 alkoxy group which may be substituted, ring A is a benzene ring which is substituted by one substituent selected from (1) a C 3-7 cycloalkyl group which may be substituted, (2) a dihydropyranyl group which may be substituted, (3) tetrahydropyranyl, which may be substituted, and (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which may be substituted, and may be substituted by additional substituents and the B ring is an imidazole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, 1,3-oxazole ring, furan ring or thiophene ring, each of which may be substituted .

[0155] Here, as "one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms," for example, a morpholine group, pyrrolyl group, dihydropyrrolyl group, pyrazolyl group, dihydropyrazolyl group is preferred as heteroatoms " , piperidyl group, azetidinyl group, pyrrolidinyl group, oxazolidinyl group, imidazolyl group, imidazolidinyl group, isoxazolyl group, pyridyl group, piperazinyl group or thiazolyl group, wherein optional substituents are as described above.

[Compound (I0-G)] [0156] Compound (I0-E) or compound (I0-F) in which

R¹ is a phenyl group which may be substituted by 1 to 5 halogen atoms,

R² is C1-10 alkoxy, o

R³ is a hydrogen atom, ring A is a benzene ring which is substituted by one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms which can be substituted by 1 to 4 substituents selected from halogen , hydroxyl group, oxo group, C1-10 alkoxy halogeno group, C1-10 alkoxycarbonyl group and C1-10 alkyl group, which may be substituted by a halogen atom and which may be further substituted by 1 or 2 substituents selected from a halogen atom and a C1-10 alkoxy group, and ring B is a pyrazole ring.

[0157] Here, as "one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and from 1 to 3 nitrogen atoms," for example, a morpholine group, pyrrolyl group, dihydropyrrolyl group, pyrazolyl group, dihydropyrazolyl group is preferred as heteroatoms " , piperidyl, azetidinyl, pyrrolidinyl, oxazolidinyl, imidazolyl or imidazolidinyl.

[0158] In another aspect of the present invention, the following compounds i.e. compounds (IO-H) and (IO-I) are preferred as compound (IO).

[Compound (IO-H)] [0159] Compound (IO) in which

R¹ means an alkyl group which may be substituted, an alkoxy group which may be substituted, a cycloalkyl group which may be substituted or an aromatic group, all of which fall within the definition of group substituents

And the substituents described above, which can be substituted,

R² is a hydroxyl group, a C 1-10 alkyl group that can be substituted, or a C 1-10 alkoxy group that can be substituted,

R³ is a hydrogen atom or a C 1-10 alkyl group that can be substituted, ring A is a 5- or 6-membered aromatic ring which can be substituted by one or more substituents selected from halogen, cyano, hydroxy, alkyl which may be substituted, an alkoxy group which may be substituted, a carbamoyl group, an alkylsulfanyl group which may be substituted, an alkylsulfinyl group, which may be substituted, a heterocyclic sulfonyl group, an amino group that may be substituted, a cycloalkyl group and a saturated heterocyclic group, and ring B is a 5-membered aromatic heterocyclic ring which may be substituted, wherein optional substituents are as described above.

[Compound (I0-I)] [0160] Compound (I0) in which ring A is a 5- to 6-membered aromatic ring (e.g., phenyl, pyridyl) which can be substituted by one or more substituents selected from ( a) halogen atoms (e.g. chlorine, fluorine, iodine) (b) cyano, (c) C1-10 alkyl which may be substituted by 1 to 3 halogen atoms (e.g. methyl, trifluoromethyl), (d) groups C3-7 cycloalkyl (e.g. methyl, trifluoromethyl), (e) a C1-10 alkoxy group which may be substituted by 1 to 3 halogen atoms (e.g. difluoromethoxy, methoxy), (f) a 5- to 10-membered heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. morpholinyl, benzimidazolyl, piperidinyl), (g) a C1-10 alkylsulfonyl group (e.g. methylsulfonyl) (h) a 5- to 10-membered heterocyclic sulfonyl group containing from 1 to 3 heteroatoms selected from a nitrogen atom, oxygen and sulfur (e.g. morpholinylsulfonyl), (i) a carbamoyl group,

R¹ is (a) a C1-10 alkyl group (e.g. isopropyl, isobutyl) or (b) halogen atoms (e.g. a chlorine, fluorine atom), a C1-10 alkyl group (e.g. methyl), a C1-10 alkoxy group (e.g. methoxy),

R² is (a) a hydroxyl group, (b) a C1-10 alkyl group (e.g. methyl) or (c) a C1-10 alkoxy group which may be substituted by one or more substituents selected from halogen atoms and a C3-7 cycloalkyl group (e.g. methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, difluoromethoxy), β

R³ is a hydrogen atom or a C 1-10 alkyl group (e.g. methyl), ring B is preferably a 5-membered nitrogen-containing aromatic heterocyclic ring containing from 1 to 3 nitrogen atoms (e.g. pyrazole, triazole, tetrazole) which may be substituted by a C 1-10 alkyl group (e.g. methyl).

[0161] When the compound (IO) is a salt, for example metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Preferable examples of metal salts include, for example, alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts; and aluminum salts. Preferable examples of the organic base salt include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'dibenzylethylenediamine. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid. Preferable examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid -toluenosulfonowym. Preferable examples of the salts with basic amino acids include salts with arginine, lysine or ornithine. Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid. Of these, salts that are pharmacologically acceptable are preferred. For example, when an acid function is present in a compound, inorganic salts including alkali metal salts (e.g., sodium salts) and alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts) and ammonium salts are preferred . On the contrary, when a basic functional group is present in the compound, for example salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or salts with organic acid such as acid salts are preferred acetic, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid.

[0162] When compound (I0) includes isomers such as tautomers, optical isomers, spatial isomers, inverse isomers and rotary isomers, one of the other isomers or mixtures are also included in the scope of the compounds of the present invention. In addition, if compound (I0) has an optical isomer, then within the scope of compound (I0) an optical isomer isolated from the racemate is included.

[0163] Compound (I0) can be obtained in crystalline form. The scope of compound (I0) may include either a single crystalline form or a crystalline mixture.

[0164] The compound of formula (I0) may be a pharmaceutically acceptable co-crystal or co-crystal salt. The terms "co-crystal" or "co-crystal salt" as used herein, means a crystalline material composed of two or more unique solids at room temperature, each having different physical properties, such as structure, melting point and fusion heat, hygroscopicity, solubility and durability. The co-crystal or co-crystal salt can be obtained according to a co-crystallization method known per se.

[0165] Compound (I0) can be provided as a solvate (e.g. hydrate) or as a non-solvate compound and both forms are within the scope of compound (IO).

[0166] Isotope-labeled compounds (for example ²H ³H ¹¹C ¹⁴C ¹⁸F ³⁵S ¹²⁵I) are also included in the scope of compound (I0).

[Production methods] [0167] The compound of the present invention and compounds as raw materials can be produced by known methods, for example using the methods shown in the following schemes. Hereinafter, "room temperature" means a temperature generally in the range of 0 to 35 ° C, and "lower temperature" means a temperature generally of -78 to 0 ° C.

[0168] Compound (I0) can be obtained, for example, by a method explained below or by a method comparable to it. The method for producing compound (I0) is explained below by explaining the methods for producing compounds (Ie), (If), (Ih), (Ii) and (Ij) falling within the scope of compound (Io). Methods for preparing compounds (Ia), (Ib), (Ic), (Id) and (Ig) are provided for comparative purposes.

[0169] The symbols used for the compounds in the reaction schemes have the same meanings as mentioned above. In the present description, the methyl (CH3) group is sometimes abbreviated as Me. Compounds in the schemes may include salts thereof in cases where salts may be formed and such salts are similar to salts of compound (Io). In addition, the compound obtained in each process can be used directly as a reaction mixture or as a crude product in subsequent reactions. However, it can be isolated from the reaction mixture according to a common method. The product itself can be easily purified by known isolation methods such as extraction, concentration, neutralization, filtration, distillation, recrystallization and chromatography. Alternatively, if the compound in the schemes is commercially available, the commercial product can be used directly and in addition, those prepared by known methods or by a comparable method can be used. If the compound contains an amino, carboxyl, hydroxyl or heterocyclic group as the raw material, this group may be protected by a protecting group that is generally used in peptide chemistry. In this case, if desired, the target compound can be obtained by removing the protecting group. The protecting group can be introduced or removed by known methods, for example based on the methods described in "Protective Groups in Organic Synthesis, 3^rd Edition "(by Theodor W. Greene, Peter GM Wuts, published in 1999 by Wiley-Interscience Corporation).

[0170] Examples "X^-"include halogen anions (e.g., chlorine anion, bromine anion, iodine anion), nitrate ion and phosphate ion.

[0171] In these methods of preparation, transformation of each R substituent¹ to R.⁹ and each substituent on ring A and B can be carried out according to a known method per se, for example the method described in "Comprehensive Organic Transformations" (by Richard C. Larock, published 1999 by Wiley-VCH).

[0172] The following individual processes may be carried out without solvent or the raw materials may be dissolved or suspended in a suitable solvent prior to the reaction. In this case, one type of solvent may be used independently or two or more solvents may be combined in a suitable ratio. Specific examples of solvents for use in the methods of making this compound are specifically provided below:

Alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol.

Ethers: diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane.

Aromatic hydrocarbons: benzene, chlorobenzene, toluene, xylene.

Saturated hydrocarbons: cyclohexane, hexane.

Amides: N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide.

Halogenated hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane.

Nitrile: acetonitrile, propionitrile.

Sulfoxides: dimethyl sulfoxide.

Aromatic organic bases: pyridine, lutidine.

Acid anhydrides: acetic anhydride.

Organic acids: formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid.

Inorganic acids: hydrochloric acid, sulfuric acid.

Esters: methyl acetate, ethyl acetate, butyl acetate.

Ketones: acetone, methyl ethyl ketone.

[0173] Specific examples of bases or deoxidizing agents that are used in the methods for producing the compound of the present invention are given below:

Inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide. Basic salts: sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate.

Organic bases: triethylamine, diisopropylethylamine, tributylamine, cyclohexyl dimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3], -5 4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7undecene, imidazole.

Metal alcoholates: sodium methoxide, sodium ethoxide, potassium tert-butoxide.

Alkali metal hydrides: sodium hydride, potassium hydride.

[0174] Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide.

[0175] Organic lithium reagents: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium.

[0176] Specific examples of acids or acid catalysts that are used in the methods for producing the compound of the present invention are given below:

Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid.

Organic acids: acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid.

Lewis acids: trifluoroboric ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride.

[0177] When "heterocyclic compounds", "carbamate compounds", "acetylene derivatives", "boronic acid derivatives" or "organocin compounds" are bonded to the A-ring containing a leaving group, the product can be prepared by a coupling reaction in the presence of a base from using both a palladium catalyst and a copper catalyst or one of them. "Heterocyclic compounds" include imidazole ring compound, pyrazole ring compound, pyrrolidine ring compound, azetidine ring compound, pyrrolidone ring compound, piperidone ring compound, "carbamate compounds" include oxazolidone ring compound, "acetylene derivatives" include cyclopropylacetylene, "boronic acid derivatives" include (1-methyl-1H-pyrazol-4-yl) boronic acid pinacol esters, "Organocin compounds" include 2- (tributylstannyl) -1,3-oxazole. [0178] As "palladium catalyst" can be used, for example, tris (dibenzylideneacetone) dipalladium (0), tetrakistriphenylphosphine palladium (0). The palladium catalyst can be used in an amount ranging from about 0.01 to 1 mole and preferably from 0.05 to 0.2 mole relative to 1 mole of the reactant. "Palladium catalyst" can be used in combination with phosphine ligands. When a phosphine ligand is used, it is used in an amount ranging from about 0.01 to 4 moles and preferably from 0.05 to 1 mole relative to 1 mole of reaction substrate. As the "phosphine ligand" there may be mentioned, for example, a phosphine ligand such as triphenylphosphine and 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene. As the "copper catalyst", for example, copper (I) iodide (CuI) and copper oxide can be used (Cu2O). "Copper catalyst" can be used in an amount ranging from about 0.1 to 1 mole and preferably from 0.1 to 0.5 mole relative to 1 mole of reactant. In addition, "copper catalyst" can be used together with a ligand such as N, N'-dimethylethane-1,2-diamine, trans-1,2-diaminocyclohexane and salicylaldoxime. Such a ligand is used in an amount ranging from about 0.1 to 4 moles and preferably from 0.1 to 2 moles relative to 1 mole of the reactant. As the base, sodium tert-butoxide or potassium phosphate can be used, and the amount is in the range of from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of the reaction substrate. It is preferred to carry out the present reaction in the absence of a solvent or in the presence of an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but for example ethers, nitriles are desired. It is desirable to carry out the reaction generally at room temperature or under reflux conditions by heating and preferably under reflux conditions by heating. The reaction time is generally in the range of 0.5 to 48 hours and preferably 1 to 24 hours.

[0179] This coupling reaction can be carried out using the methods described in "Cross-Coupling Reactions: A Practical Guide (Topics in Current Chemistry)" (Springer) "Experimental Organic Metallic Chemistry for Synthesizing Chemists" (Kodansha) and "Organic Synthesis using Transition Metals "(Kagaku Dojin) or by a comparable method.

[0180] Compounds (Ie), (If), (Ih), (Ii) and (Ij), each of which is included in the scope of compound (I0) can be obtained by the method of production E, method of production F, method of preparation H, method of producing I or method of producing J as explained below. Compounds (Ia), (Ib), (Ic), (Id) and (Ig) and methods for preparing A, B, C, D and G are given for comparative purposes.

[0181] The symbols in each general formula in the reaction schemes have the same meanings as mentioned above unless specifically indicated otherwise.

[Production method A] [0182]

<img file="PL2393360T3_D0006.tif" />

[0183]

<img file="PL2393360T3_D0007.tif" />

[0184]

<img file="PL2393360T3_D0008.tif" />

[Production method D] [0185]

<img file="PL2393360T3_D0009.tif" />

(X) (XV)

<img file="PL2393360T3_D0010.tif" />

(XVI) (W) [Production method E] [0186]

<img file="PL2393360T3_D0011.tif" />

[0187]

<img file="PL2393360T3_D0012.tif" />

[Production method G] [0188]

<img file="PL2393360T3_D0013.tif" />

[0189]

<img file="PL2393360T3_D0014.tif" />

[Production method I] [0190]

<img file="PL2393360T3_D0015.tif" />

[Production method J]

<img file="PL2393360T3_D0016.tif" />

[0192] Process 1 is a process for producing compound (III) by reacting compound (II) with a diazotizing agent. If desired, the reaction can be carried out in the presence of an acid.

[0193] Examples of the diazotizing agent are the following: alkali metal nitrates such as sodium nitrate and potassium nitrate; nitric acid C 3-6 alkyl esters such as t-butyl nitrate and isoamyl nitrate; nitrosyl chloride, nitrosyl sulfate and nitric oxide (I). Of these, sodium nitrate is desirable from such a point of view that it can be obtained easily at low cost. In addition, nitric (III) acid alkyl esters are desirable in such a way that reactivity is increased. In this case, since the alkali metal nitrate is solid at room temperature, it is dissolved earlier in water before use. [0194] As "acid", for example, hydrochloric acid, sulfuric acid and acetic acid can be used, and they can also be used as a mixture.

[0195] From the viewpoint of increasing reactivity and economic efficiency, the amount of diazotizing agent ranges from 1 to 5 moles and preferably from 1 to 2 moles relative to 1 mole of Compound (II). It is desirable to carry out the reaction generally at room temperature or at a lower temperature and preferably at a temperature in the range from -30 ° C to 0 ° C.

[0196] The reaction time generally ranges from 1 minute to 3 hours and preferably from 1 minute to 1 hour.

[0197] It is preferred to carry out the present reaction in the absence of a solvent or in the presence of an inert solvent in the reaction. These solvents are not limited as long as the reaction proceeds, but water is preferred.

[0198] Process 2 is a process for producing compound (V), compound (IX), compound (XVIII) or compound (XXVIII) by placing compound (III) together with compound (IV), compound (VIII), compound (XVII) or compound (XXVII).

[0199] This process can be carried out by the method described in Tetrahedron Lett., 2008, 49 (14), 2262-2264 or by a comparable method. If desired, the reaction can be carried out in the presence of a base.

[0200] The amount of compounds (IV), (VIII), (XVII) or (XXVII) used ranges from about 1 to 5 moles and preferably from 1 to 2 moles relative to 1 mole of compound (III).

For example, sodium acetate may be used as the "base".

[0202] The amount of "base" used is generally in the range of 1 to 10 equivalents and preferably 2 to 6 equivalents relative to compound (III). [0203] It is preferred to carry out this reaction in the absence of a solvent or in the presence of an inert solvent in the reaction These solvents are not limited as long as the reaction proceeds, but a mixed solvent consisting of alcohols and water is desired.

[0204] It is desirable to carry out the reaction generally at room temperature or at a lower temperature with cooling in an ice bath.

[0205] The reaction time is generally in the range of 5 seconds to 24 hours and is preferably in the range of 5 seconds to 1 hour.

[0206] R⁴ is a C1-10 alkyl group which may be substituted and preferably a methyl group or an ethyl group. In this process, R² is a C1-10 alkyl group which may be substituted or a C1-10 alkoxy group which may be substituted, wherein optional substituents are as described above.

[0207] Process 3 is a process for producing compound (VI), compound (X), compound (XIX), compound (XXIII) or compound (XXXIV) from compound (V), compound (IX), compound (XVIII), compound ( XXII) or compound (XXXIII). The reaction can be carried out in the presence of N, N-dimethylformamide dimethyl acetal as a solvent.

[0208] This process can be carried out by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a comparable method. [0209] It is desirable to conduct the reaction generally under reflux conditions by heating and preferably at a temperature from 100 ° C to 150 ° C.

[0210] The reaction time is generally in the range of 1 to 10 hours and preferably 1 to 5 hours.

[0211] Process 4 is a process for producing compound (Ia), compound (Ie) or compound (XXXV) by placing compound (VII) together with compound (VI), compound (XXIII) or compound (XXXIV).

[0212] The amount of compound (VII) used ranges from about 1 to 10 moles and preferably from about 2 to 5 moles relative to 1 mole of compound (VI), compound (XXIII) or compound (XXXIV).

[0213] It is preferred to carry out the reaction in the absence of a solvent or in the presence of an inert solvent in the reaction. The solvent used is not limited as long as the reaction proceeds, but alcohols, organic acids or mixtures of these solvents are desired.

[0214] It is desirable to carry out the reaction generally in an ice bath, at room temperature or under reflux conditions by heating and preferably at a temperature from 0 ° C to 150 ° C.

[0215] The reaction time is generally in the range of 0.1 to 10 hours and preferably 0.5 to 5 hours.

[0216] This process can be carried out by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a comparable method. [0217] In this process, R¹ means a C 1-10 alkyl group which may be substituted, a C 3-7 cycloalkyl group which may be substituted or an aromatic group falling within the definition of the substituents of group A of the substituents described above and which may be substituted, wherein optional substituents are as described above. [0218] Process 5 is a method of producing compound (XI) by reacting compound (X) with hydrazine, a method of producing compound (XIII) by reacting compound (X) with ammonia, or a method of producing compound (XV) by reacting compound (X ) with an amine compound (XII).

[0219] The amount of hydrazine, ammonia and amine compound (XII) used ranges from about 1 to 10 moles and preferably from about 2 to 5 moles relative to 1 mole of compound (X).

[0220] It is preferred if the reaction is carried out in the absence of a solvent or in the presence of an inert solvent in the reaction. The solvent is not limited as long as the reaction proceeds but for example alcohols or ethers are desired.

[0221] It is desirable to conduct the reaction generally under heating conditions and preferably at a temperature of 50 ° C to 100 ° C.

[0222] The reaction time is generally in the range of 1 to 10 hours and preferably 1 to 5 hours.

[0223] This process can be carried out by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a comparable method.

[0224] In addition, a microwave heating method or a heating method in the presence of trimethylaluminum as activator can be used.

[0225] The reaction temperature when heated under microwave conditions is generally in the range from 50 ° C to 150 ° C and preferably from 100 ° C to 130 ° C. The reaction time is generally in the range of 10 to 60 minutes and preferably 10 to 20 minutes. It is preferred to carry out the reaction in the absence of a solvent or using an inert solvent in the reaction. The solvent is not limited as long as the reaction proceeds but for example alcohols or ethers are desired.

[0226] If the reaction is carried out in the presence of trimethylaluminum as activator, trimethylaluminum is used in an amount ranging from about 1 to 5 moles and preferably from about 1 to 3 moles relative to 1 mole of compound (X). It is preferred to carry out the reaction in the absence of a solvent or using an inert solvent in the reaction. The solvent is not limited as long as the reaction proceeds, but methylene chloride is desired. It is desirable to carry out the reaction generally under heating and preferably at a temperature of 50 ° C to 100 ° C. The reaction time is generally in the range of 1 to 15 hours and preferably 1 to 10 hours.

[0227] Process 6 is a method for producing compound (Ib) by placing compound (XI) together with the amine compound (XII).

[0228] In the case where R⁵ is hydrogen, compound (XI) is reacted with N, N-dimethylformamide dimethyl acetal or a similar compound and then reacted with an amine compound (XII) under acidic conditions without isolation to give compound (Ib). However, if R⁵ is a methyl group, compound (XI) is reacted with N, N-dimethylacetamide dimethyl acetal and the reaction is carried out with the amine compound (XII) under acidic conditions as mentioned above to give compound (Ib).

[0229] The amount of N, N-dimethylformamide dimethyl acetal or N, N-dimethylacetamide dimethyl acetal used ranges from about 1 to 5 moles and preferably from about 1 to 2 moles relative to 1 mole of compound (XI).

[0230] It is desirable to conduct the reaction generally under heating conditions and preferably at a temperature of 50 ° C to 100 ° C.

[0231] The reaction time is generally in the range of 0.5 to 3 hours and preferably 0.5 to 1 hour.

[0232] It is preferred to carry out the reaction in the absence of a solvent or using an inert solvent in the reaction. The solvent is not limited as long as the reaction proceeds, but nitriles are desirable, for example.

[0233] The amount of amine compound (XII) used ranges from about 1 to 5 moles and preferably from 1 to 2 moles relative to 1 mole of compound (XI).

[0234] As "acid", for example, acetic acid can be used.

[0235] Regarding the amount of acid used, it is desirable to use the same amount as the acetonitrile used as the solvent in the above-mentioned reaction.

[0236] It is desirable to carry out the reaction generally under heating conditions and preferably at a temperature from 100 ° C to 130 ° C.

[0237] The reaction time is generally in the range of 0.5 to 3 hours and preferably 0.5 to 1 hour.

[0238] This process can be carried out using the method described in Org. Lett., 2004, 6 (17), 2969-2971 or by a comparable method.

[0239] Process 7 is a process for producing compound (XIV) from compound (XIII). The product can be made in the presence of N, N-dimethylformamide dimethyl acetal as a solvent.

[0240] It is desirable to conduct the reaction generally under heating conditions and preferably at a temperature from 100 ° C to 150 ° C.

[0241] The reaction time is generally in the range of 0.1 to 5 hours and preferably 0.1 to 1 hour.

[0242] This process can be carried out using the method described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 or by a comparable method.

[0243] Process 8 is a method for producing compound (Ic) by placing compound (XIV) together with a hydrazine compound (VII). The reaction can be carried out in the presence of an organic acid.

[0244] The amount of hydrazine compound (VII) used ranges from about 1 to 5 moles and preferably from 1 to 2 moles relative to 1 mole of compound (XIV).

[0245] Acetic acid, for example, can be used as "organic acid".

[0246] The amount of organic acid used is similar to the amount when it is usually used as a solvent.

[0247] It is desirable to conduct the reaction generally under heating conditions and preferably at a temperature from 100 ° C to 130 ° C.

[0248] The reaction time is generally in the range of 0.5 to 3 hours and preferably 0.5 to 1 hour.

[0249] This process can be carried out using the method described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 or by a comparable method.

[0250] Process 9 is a process for producing compound (XVI) from compound (XV). The reaction can be carried out in the presence of 1H-benzo [d] [1,2,3] triazole and an acid halide.

[0251] It is preferred to carry out the reaction in the absence of a solvent or using an inert solvent in the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example halogenated hydrocarbons are desired.

[0252] The amount of 1H-benzo [d] [1,2,3] triazole used is in the range of about 1 to 10 moles and preferably 1 to 5 moles relative to 1 mole of compound (XV).

[0253] As an "acid halide", for example, thionyl chloride may be used.

[0254] The amount of "acid halide" used is in the range of about 1 to 5 equivalents and preferably 1 to 2 equivalents relative to compound (XV). [0255] It is desirable to conduct the reaction under reflux conditions by heating and it is also possible to carry out the reaction in a short time under microwave conditions. If the reaction is carried out under microwave conditions, the reaction time ranges from 0.1 to 1 hour at 80 watts and preferably from 0.1 to 0.3 hours.

[0256] This process can be carried out by the method described in Synthesis, 2007, 1204-1208 or by a comparable method.

[0257] Process 10 is a process for producing compound (Id) from compound (XVI). The product can be prepared by reacting acid as well as sodium azide in the presence of a phase transfer catalyst.

[0258] It is preferred to carry out the reaction using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but it is desirable to use, for example, a halogenated hydrocarbon mixed with water.

[0259] As "phase transfer catalyst, for example, tetrabutylammonium bromide can be used.

[0260] The amount of "phase transfer catalyst" used is in the range of from about 0.1 to 1 equivalent and preferably from 0.1 to 0.3 equivalent relative to compound (XVI).

[0261] The amount of sodium azide used is in the range of about 1 to 5 moles and preferably 1 to 3 moles relative to 1 mole of Compound (XVI).

[0262] As "acid", for example, organic acids can be used.

[0263] The amount of "acid" used is in the range of about 1 to 5 equivalents and preferably 1 to 2 equivalents relative to compound (XVI).

[0264] The reaction temperature may range from 0 ° C to 100 ° C and is preferably carried out at room temperature.

[0265] The reaction time is generally in the range of 1 to 48 hours and preferably 10 to 24 hours.

[0266] This process can be carried out by the method described in Synthesis, 2007, 1204-1208 or by a comparable method.

[0267] Process 11 is a process for producing compound (XX) or compound (XXXI) from compound (XIX) or compound (XXX). The reaction can be carried out under acidic or basic conditions. It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but it is desirable to use, for example, alcohol, a solvent mixed with water, and ethers.

[0268] As "acid", for example, inorganic acids can be used.

As a "base", for example, inorganic bases such as sodium hydroxide or potassium hydroxide can be used. In addition, lithium hydroxide can also be used.

[0270] The amount of acid or base used ranges from about 1 to 10 moles and preferably 1 to 5 moles relative to 1 mole of compound (XIX) or compound (XXX). [0271] It is desirable to carry out the reaction generally at room temperature or under heating conditions and preferably at room temperature.

[0272] The reaction time is generally in the range of 1 to 48 hours and preferably 3 to 10 hours.

[0273] Process 12 is a process for producing compound (XXI) or compound (XXXII) from compound (XX) or compound (XXXI). The product can be made using N, O-dimethylhydroxylamine hydrochloride with a condensing agent in the presence of such a triethylamine base or N, N-diisopropylethylamine. Alternatively, the carboxylic acid group of the substrate is converted to the corresponding acid halide, which is then reacted with N, Odimethylhydroxylamine hydrochloride to form target products.

As "condensing agent", for example, 1-ethyl3- (3-dimethylaminopropyl) carbodiimide hydrochloride can be used in the presence of 1-hydroxybenzotriazole.

[0275] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but for example nitriles, ethers and amides are desired.

[0276] The amount of condensation agent used is in the range of from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XX) or compound (XXXI).

[0277] A base such as triethylamine or N, N-diisopropylethylamine is preferably used in an amount ranging from about 1 to 10 moles and preferably from 2 to 3 moles relative to 1 mole of compound (XX) or compound (XXXI).

[0278] It is desirable to carry out the reaction generally at room temperature or under heating conditions and preferably at room temperature.

[0279] The reaction time is generally in the range of 1 to 48 hours and preferably 5 to 10 hours.

[0280] The reaction with the acid halide is carried out in the presence of a base such as triethylamine using N, O-dimethylhydroxylamine hydrochloride to synthesize the target product.

[0281] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but for example ethers, esters or amides are desired.

[0282] The amount of base such as triethylamine ranges from about 1 to 10 moles and preferably from 2 to 3 moles relative to 1 mole of compound (XX) or compound (XXXI). [0283] It is generally desirable to carry out the reaction during cooling in an ice bath or at room temperature and preferably with cooling in an ice bath.

[0284] The reaction time is generally in the range of 0.5 to 5 hours and preferably 1 to 3 hours.

[0285] In addition, compound (XXI) or compound (XXXII) can be produced by reacting compound (XIX) or compound (XXX) with trimethylaluminum and N, Odimethylhydroxylamine hydrochloride in the presence of an organic base. The amount of organic base, trimethylaluminum and N, O-dimethylhydroxylamine hydrochloride is in the range of about 1 to 10 moles and preferably 2 to 5 moles relative to 1 mole of compound (XIX) or compound (XXX). It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but for example halogenated hydrocarbons are desired. It is generally desirable to carry out the reaction with cooling in an ice bath or at room temperature and preferably with cooling in an ice bath. The reaction time is generally in the range of 1 to 24 hours and preferably 1 to 5 hours.

[0286] Process 13 is a process for producing compound (XXII) or compound (XXXIII) from compound (XXI) or compound (XXXII). The product can be made using a "alkylating agent" such as a Grignard reagent or organic lithium reagent.

[0287] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but ethers are desired, for example.

[0288] The amount of "alkylating agent" is in the range of about 1 to 10 moles and preferably 2 to 3 moles relative to 1 mole of compound (XXI) or compound (XXXII). [0289] It is desirable to carry out the reaction generally in at -78 ° C or during cooling in an ice bath and preferably at -78 ° C.

η [0290] R⁷ is a hydrogen atom or a C 1-10 alkyl group which may be substituted as described above and preferably a hydrogen atom or a methyl group.

ο [0291] R⁸ is a hydrogen atom or a C 1-10 alkyl group which may be substituted as described above and preferably a hydrogen atom or a methyl group.

[0292] The reaction time is generally in the range of 1 to 10 hours and preferably 1 to 3 hours.

[0293] Process 14 is a process for producing compound (XXIV) from compound (XX). The product can be prepared using diphenylphosphoryl azide in the presence of a base such as triethylamine.

[0294] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds. For example, when tert-butanol is used as the solvent, the tert-butyl carbamate derivative is temporarily obtained and its hydrolysis is carried out under acidic conditions to produce compound (XXIV). In addition, when toluene is used as the solvent, the isocyanate as intermediate is hydrolyzed with an aqueous sodium hydroxide solution to produce compound (XXIV).

[0295] The amount of diphenylphosphoryl azide is in the range of about 1 to 10 moles and preferably 1 to 3 moles relative to 1 mole of Compound (XX).

[0296] The amount of triethylamine ranges from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of Compound (XX).

[0297] It is desirable to carry out the reaction generally at room temperature or under reflux conditions by heating and preferably under reflux conditions by heating.

[0298] The reaction time is generally in the range of 1 to 20 hours and preferably 1 to 10 hours.

[0299] This process can be carried out by the method described in Tetrahedron 1974, 30, 2151-2157 or by a comparable method.

[0300] Process 15 is a method of producing compound (XXV) from compound (XXIV). The product can be made using nitrate (III) in the presence of copper salts. [0301] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but for example amides are desired.

[0302] As a "copper salt", copper (II) bromide (CuBr2) can be used and its amount ranges from about 1 to 5 moles and preferably 1 to 2 moles relative to 1 mole of compound (XXIV).

[0303] As "(III) nitrate", isoamyl nitrate or pentyl nitrate (III) nitrate can be used and the amount ranges from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of the compound (XXIV).

[0304] It is desirable to carry out the reaction generally in an ice bath, at room temperature or under heating conditions and preferably at a temperature in the range of 0 to 70 ° C.

[0305] The reaction time is generally in the range of 1 to 10 hours and preferably 1 to 5 hours.

[0306] This process can be carried out by the method described in US5059599 or by a comparable method.

[0307] Process 16 is a process for producing compound (If) from compound (XXV) and compound (XXVI). The product can be prepared using a palladium catalyst in the presence of a base.

[0308] The amount of compound (XXVI) used ranges from about 1 to 10 moles and preferably from about 1 to 3 moles relative to 1 mole of compound (XXV).

As a "base", potassium acetate or potassium carbonate can be used and the amount is in the range of about 1 to 10 moles and preferably 1 to 3 moles relative to 1 mole of compound (XXV).

As "palladium catalyst", bis [di-tert-butyl (4-dimethylaminophenyl) phosphino] dichloropalladium (II) or tetrakis (triphenylphosphine) palladium can be used and its amount ranges from about 0.01 to 0.5 mole and preferably from 0.03 to 0.1 mole relative to 1 mole of compound (XXV).

[0311] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but alcohols, a solvent-water mixture, aromatic hydrocarbons, ethers, amides are desired, for example.

[0312] It is desirable to carry out the reaction generally at room temperature or under reflux conditions by heating and preferably under reflux conditions by heating.

[0313] The reaction time is generally in the range of 5 to 48 hours and preferably 10 to 20 hours.

[0314] This process can be carried out using the method described in Org. Lett., 2006, 8, 1787-1789 or by a comparable method.

[0315] R.⁹ is an alkoxy group which may be substituted or a hydroxyl group.

[0316] Process 17 is a process for producing compound (XXIX) from compound (XXVIII) and the reaction can be carried out in the presence of a base.

[0317] As a base, basic salts, organic bases, metal alkoxides or metal amides can be used, and potassium carbonate or sodium methoxide is desired. The amount of base is in the range of about 1 to 10 moles and preferably 1 to 3 moles relative to 1 mole of compound (XXVIII). It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but for example ethers or amides are desired. In general, it is desirable to carry out the reaction at room temperature or reflux conditions by heating and preferably at room temperature.

[0318] The reaction time is generally in the range of 1 to 24 hours and preferably 2 to 4 hours.

[0319] Process 18 is a process for producing compound (XXX) or compound (Ig) from compound (XXIX) or compound (XXXVI).

[0320] Methylation can be carried out under conditions where trimethylsilyl diazomethane or methyl iodide is used in the presence of a base.

[0321] When the reaction is carried out using trimethylsilyl diazomethane, trimethylsilyl diazomethane is used in an amount ranging from about 10 to 50 moles and preferably from 5 to 20 moles relative to 1 mole of compound (XXIX) or compound (XXXVI) with using a solvent such as methanol. In general, it is desirable to carry out the reaction with cooling in an ice bath or at room temperature and preferably with cooling in an ice bath.

[0322] The reaction time is generally in the range of 1 to 5 hours and preferably 1 to 2 hours.

[0323] In the case where methyl iodide is used in the presence of a base, the reaction may be carried out using an ether solvent in the presence of sodium hydroxide.

[0324] Methyl iodide is used in an amount ranging from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXIX) or compound (XXXVI). In addition, a base such as sodium hydroxide is also used in an amount ranging from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXIX) or compound (XXXVI). In general, it is desirable to carry out the reaction with cooling in an ice bath or at room temperature and preferably with cooling in an ice bath.

[0325] The reaction time is generally in the range of 1 to 5 hours and preferably 1 to 2 hours.

[0326] Process 19 is a process for producing compound (XXXVI) from compound (XXXV) and the product can be obtained using trimethylsilyl chloride in the presence of sodium iodide.

[0327] The amount of sodium iodide is in the range of about 1 to 10 moles and preferably 1 to 5 moles relative to 1 mole of Compound (XXXV). The amount of trimethylsilyl chloride is in the range of about 1 to 10 moles and preferably 1 to 5 moles relative to 1 mole of Compound (XXXV).

[0328] It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but for example nitriles are desired. In general, it is desirable to carry out the reaction at room temperature or under reflux conditions by heating and preferably under reflux conditions by heating. The reaction time is generally in the range of 1 to 20 hours and preferably 3 to 10 hours.

[0329] Process 20 is a process for producing compound (XXXVII) from compound (XIX) and the product can be obtained using a suitable reducing agent. [0330] As a "reducing agent", lithium aluminum hydride, diisobutyl aluminum hydride may be used. It may be used in an amount ranging from about 1 to 10 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XIX). It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but ethers are desired, for example. It is generally desirable to carry out the reaction at -78 ° C or with cooling in an ice bath and preferably at -78 ° C.

[0331] The reaction time is generally in the range of 0.5 to 5 hours and preferably 1 to 3 hours.

[0332] This process can be carried out by the method described in Comprehensive Organic Transformations (WILEY-VCH) or by a comparable method. [0333] Process 21 is a process for producing compound (XXXVIII) from compound (XXXVII) and the product can be prepared using appropriate oxidation.

[0334] As "oxidation", for example, Swern oxidation or oxidation using an oxidizing agent such as a complex of sulfur trioxide and pyridine, pyridinium chlorochromate can be used. When the oxidation is carried out using an oxidizing agent, its amount ranges from about 1 up to 10 moles and preferably 1 to 3 moles relative to 1 mole of Compound (XXXVII). It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but dimethyl sulfoxide, halogenated hydrocarbons, ethers and esters are desired, for example. In general, it is desirable to carry out the reaction at low temperature or at room temperature. The reaction time is generally in the range of 1 to 10 hours and preferably 1 to 3 hours.

[0335] This process can be carried out by the method described in Comprehensive Organic Transformations (WILEY-VCH) or Oxidation in Organic Chemistry (American Chemical Society) by a comparable method.

[0336] Process 22 is a method of producing compound (Ih) from compound (XXXVIII). Using α-tosylbenzyl isocyanide (Organic Syntheses, Coll. Vol. 10, p692 (2004): Vol. 77, p198 (2000)), a 1,3-oxazole compound or 1,3-imidazole compound can be produced. In the preparation of a "1,3-oxazole compound", the reaction is carried out in the presence of a base such as potassium carbonate. In contrast, in the preparation of the "1,3-imidazole compound", the reaction is carried out in the presence of a base such as potassium carbonate in the presence of aqueous ammonia or an amine such as methylamine.

[0337] A base such as potassium carbonate, aqueous ammonia or methylamine is used in an amount ranging from about 1 to 10 moles and preferably from 1 to 3 moles relative to compound (XXXVIII). It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds, but for example ethers, nitriles and amides are desired. In general, it is desirable to conduct the reaction at low temperature or room temperature and preferably at room temperature.

[0338] The reaction time is generally in the range of 5 to 30 hours and preferably 5 to 15 hours.

[0339] This process can be carried out by the method described in New Edition: Heterocyclic Compounds (Kodansha) or by a comparable method.

[0340] Process 23 is a method of producing compound (Ii) from compound (XXIV). Provided that the reaction proceeds, it is not particularly limited, but after reaction with an aqueous solution of glyoxal in an alcoholic solvent, under acidic conditions, compound (XXIV) can be reacted with ammonium chloride and benzaldehyde to obtain compound (II).

[0341] The aqueous solution of glyoxal is used in an amount ranging from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXIV). In general, it is desirable to conduct the reaction at low temperature or room temperature conditions and preferably at room temperature conditions. [0342] The reaction time is generally in the range of 5 to 30 hours and preferably 10 to 20 hours.

[0343] Benzaldehyde and ammonium chloride are used in an amount ranging from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXIV). The acid used is not particularly limited as long as the reaction proceeds but for example phosphoric acid is desired. In general, it is desirable to conduct the reaction at room temperature or under reflux conditions by heating and preferably under reflux conditions by heating. The reaction time is generally in the range of 5 to 40 hours and preferably 20 to 30 hours.

[0344] This process can be carried out by the method described in New Edition: Heterocyclic Compounds (Kodansha) or by a comparable method.

[0345] Process 24 is a method for producing compound (XXXIX) from compound (XXV). Provided the reaction proceeds, it is not particularly limited, but the product can be prepared by reacting compound (XXV) with trimethylsilylacetylene in an ether solvent such as tetrahydrofuran in the presence of a palladium catalyst and a copper catalyst as well as a base. As the palladium catalyst, for example, bis (triphenylphosphine) palladium (II) dichloride can be used. The palladium catalyst is used in an amount ranging from about 0.01 to 1 mole and preferably from 0.05 to 0.2 mole relative to 1 mole of compound (XXV). In addition, a palladium catalyst is used together with a phosphine ligand such as triphenylphosphine. The phosphine ligand is used in an amount ranging from about 0.01 to 1 mole and preferably from 0.05 to 0.2 mole relative to 1 mole of compound (XXV). As a copper catalyst, for example, copper (I) iodide (CuI) can be used. The copper catalyst is used in an amount ranging from about 0.1 to 1 mole and preferably from 0.1 to 0.5 mole relative to 1 mole of compound (XXV). Trimethylsilylacetylene is used in an amount ranging from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXV). The reaction is carried out in the presence of a base such as triethylamine, and the amount of base used is in the range of from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of compound (XXV). In general, it is desirable to conduct the reaction by heating at a temperature in the range from 40 to 60 ° C.

[0346] The reaction time is generally in the range of 1 to 10 days and preferably 5 to 7 days.

[0347] This process can be carried out by the method described in Tetrahedron Lett., 1975, 16, 4467-4470 or by a comparable method.

[0348] Process 25 is a method of producing compound (XL) from compound (XXXIX). Provided that the reaction proceeds, it is not particularly limited, but the product can be prepared by reacting compound (XXXIX) with an aqueous sodium hydroxide solution or a fluoride ion such as tetrabutylammonium fluoride in an alcohol or ether as solvent. The amount of aqueous sodium hydroxide or fluoride ion solution ranges from about 1 to 100 moles or more and preferably from 1 to 3 moles relative to 1 mole of compound (XXXIX). In general, it is desirable to carry out the reaction with cooling in an ice bath or at room temperature and preferably at room temperature. The reaction time is generally in the range of 0.5 to 5 hours and preferably 1 to 3 hours.

[0349] Process 26 is a method for producing compound (Ij) from compound (XL). Provided that the reaction proceeds, it is not particularly limited, but the product can be prepared by reacting compound (XL) with N-hydroxybenzenecarboximidoyl chloride in ether as a solvent. Nhydroxybenzenecarboximidoyl chloride is used in an amount ranging from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of Compound (XL). The present reaction is carried out in the presence of a base such as triethylamine and the amount of base used is in the range of from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of Compound (XL). In general, it is desirable to carry out the reaction with cooling in an ice bath or at room temperature and preferably at room temperature. The reaction time is generally in the range of 1 to 48 hours and preferably 5 to 20 hours.

[0350] This process can be carried out using the method described in "New Edition:

Heterocyclic Compounds' (Kodansha) or by a comparable method.

[0351] Compound (Ie) wherein R² means a halogen atom (e.g. a bromine atom) can be produced by the following method. First, compound (V) is reacted with a reagent such as N, N-dimethylformamide dimethyl acetal

2 to obtain compound (XXII) in which R² and R⁷ are hydrogen atoms. The amount of reagent such as N, N-dimethylformamide dimethyl acetal is from about 1 to 5 moles, preferably from 1 to 2 moles relative to 1 mole of Compound (V). It is desirable that this reaction be carried out using an inert solvent (e.g., amides). It is desirable that the reaction be carried out at room temperature or with heating and preferably at a temperature in the range from 40 to 100 ° C. The reaction time is generally in the range of 1 to 20 hours and preferably 1 to 10 hours. Then, the obtained compound (XXII) is reacted with a halogen molecule (e.g. a bromine molecule) to introduce a halogen atom in the R position² relationship (XXII). The amount of halogen molecule used is in the range of from about 1 to 5 moles and preferably from about 1 to 2 moles relative to 1 mole of Compound (XXII). It is desirable that this reaction be carried out using an inert solvent (e.g. organic acids). It is desirable that this reaction be carried out at room temperature or at a lower temperature and preferably at room temperature. The reaction time is generally in the range of 1 to hours and preferably 1 to 3 hours.

ο [0352] Compound (Ie) wherein R⁸ A C1-10 alkyl group (e.g., a methyl group) can be produced by the following method. To begin with, compound (XXII) is reacted with a reagent such as N, N-dimethylacetamide dimethyl acetal to obtain compound (XXIII). The amount of N, N-dimethylacetamide dimethyl acetal used ranges from about 1 to 30 moles and preferably 5 to 20 moles relative to 1 mole of Compound (XXII). This reaction is preferably carried out without using a solvent or using an inert solvent in the reaction. In addition, it is desirable to conduct the reaction under reflux conditions by heating or it is possible to heat under microwave conditions. The reaction temperature when heated under microwave conditions is generally in the range of 50 ° C to 150 ° C and is preferably carried out at a temperature in the range of 100 ° C to 130 ° C. The reaction time is generally in the range of 1 to 60 minutes and preferably 3 to 20 minutes.

ο [0353] Compound (Ie) wherein R⁸ a C1-10 alkyl group which is substituted by a fluorine atom (e.g. a trifluoromethyl group) can be produced by the following method. To begin with, compound (XXII) is reacted with an ester having an alkyl group substituted with a fluorine atom (e.g. ethyl trifluoroacetate) under basic conditions. The amount of ester used is in the range of 1 to 20 moles and preferably 1 to 10 moles relative to 1 mole of Compound (XXII). This reaction is carried out in the presence of a base such as sodium methoxide and the amount of base used ranges from about 1 to 5 moles and preferably from 1 to 3 moles relative to 1 mole of Compound (XXII). It is desirable to carry out this reaction using an inert solvent (e.g. ethers). It is desirable to conduct the reaction under ice-cooling conditions or at room temperature and preferably at room temperature. The reaction time is generally in the range of 0.5 to 7 days and preferably 1 to 3 days. In addition, compound (Ie) can be produced by placing the reaction product together with compound (VII). The amount of compound (VII) used ranges from about 1 to 10 moles and preferably from about 2 to 5 moles relative to 1 mole of raw material. It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but for example alcohols and organic acids or mixed solvents thereof are desired. It is desirable to carry out the reaction under ice-cooling conditions or at room temperature or during heating and preferably at a temperature in the range from 0 ° C to 150 ° C. The reaction time is generally in the range of 0.1 to 10 hours and preferably 0.5 to 5 hours. This process can be carried out by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a comparable method.

η [0354] Compound (Ie) in which R⁷ is a halogen atom (for example a fluorine atom) η

can be produced by reacting compound (Ie) wherein R⁷ is hydrogen with a reagent such as a halogenating agent. For example, when a fluorine atom is introduced, bis (tetrafluoroborate) 1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane as a fluorinating agent (hereinafter referred to as Selectfluor). The amount of Selectfluor used is in the range of from about 1 to 30 moles and preferably 5 to 20 moles relative to 1 mole of Compound (Ie). This reaction is preferably carried out using an inert solvent (e.g. nitriles). In addition, it is desirable to conduct the reaction under ice-cooling conditions or at room temperature and preferably at room temperature. The reaction time is generally in the range of 1 to 20 days and preferably 5 to 15 days.

η [0355] Compound (Ie) wherein R⁷ A C1-10 alkyl group (e.g., a methyl group) can be produced by the following reaction. To begin with, compound (XXII) is reacted with an ester (e.g., methyl formate) under basic conditions. The ester also works as a solvent. This reaction is carried out in the presence of a base, such as sodium methoxide, and the amount of base used is in the range of about 1 to 5 moles and preferably 1 to 3 moles relative to 1 mole of Compound (XXII). In general, it is desirable to conduct the reaction under ice-cooling conditions or at room temperature and preferably at room temperature. The reaction time is generally in the range of 1 to 20 hours and preferably 2 to 10 hours.

[0356] Compound (Ie) can be produced by sequentially placing the reaction product together with compound (VII). The amount of compound (VII) used ranges from about 1 to 10 moles and preferably from about 2 to 5 moles relative to 1 mole of raw material. It is preferred to carry out this reaction without using a solvent or using an inert solvent in the reaction. The solvent used is not particularly limited as long as the reaction proceeds but, for example, alcohols and organic acids or mixtures of these solvents are preferred. In general, it is desirable to carry out the reaction under ice-cooling or room temperature or reflux conditions by heating and preferably at a temperature in the range of from 0 ° C to 150 ° C. The reaction time is generally in the range of 0.1 to 10 hours and preferably 0.5 to 5 hours. This process can be carried out by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a comparable method.

[0357] If the raw material compounds contain an amino group, a carboxyl group, a hydroxyl group as a substituent, in each reaction in the processes for producing said compounds (Ia), (Ib), (Ic), (Id), (Ie), (If ), (Ig), (Ih), (Ii) and (Ij) or their salts and in each reaction in the synthesis of compounds that are raw materials, a protecting group can be introduced into these groups which is usually used in peptide chemistry. If preferred, the protecting group is removed after the reaction to allow the target compound to be obtained.

[0358] As an protecting group for an amino group, for example, formyl and the following groups can be used which can be suitably substituted: C1-10 alkylcarbonyl (e.g. acetyl, ethylcarbonyl), phenylcarbonyl, C1-10 alkyloxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl, C7-10 aralkylcarbonyl (e.g. benzylcarbonyl), trityl, phthaloyl or N, N-dimethylaminomethylene. Substituents used may include a halogen atom (e.g. fluorine, chlorine, bromine, iodine), C1-10 alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, butylcarbonyl), nitro group. The number of substituents is in the range of 1 to 3.

[0359] As a protecting group for a carboxyl group, for example, the following groups can be used that can be appropriately substituted: C 1-10 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl) , phenyl, trityl or silyl. Substituents used may include halogen (e.g. fluorine, chlorine, bromine, iodine), formyl, C1-10 alkylcarbonyl (e.g. acetyl, ethylcarbonyl, butylcarbonyl), nitro. The number of substituents is in the range of 1 to 3.

[0360] As a protecting group for a hydroxyl group, for example, the following groups can be used that can be appropriately substituted: C 1-10 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl) , phenyl, C7-10 aralkyl (e.g. benzyl), formyl, C1-10 alkylcarbonyl (e.g. acetyl, ethylcarbonyl), phenyloxycarbonyl, benzoyl, C7-10 aralkylcarbonyl (e.g. benzylcarbonyl), pyranyl, furanyl or silyl. Substituents used may include halogen (e.g. fluorine, chlorine, bromine, iodine), C1-10 alkyl (e.g. methyl, ethyl, npropyl), phenyl, C7-10 aralkyl (e.g. benzyl), nitro. The number of substituents is in the range of 1 to 4.

[0361] In addition, as a method of deprotection, a known method or comparable method can be used. For example, an acid, alkali, reducing agent, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate treatment can be used.

[0362] In each reaction in the methods for producing said compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij) or their salts, and in each reaction in the synthesis of compounds that are raw materials, solvents that are commonly known may be used during the reaction.

[0363] For example, the following commonly known solvents may be used:

ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane;

esters such as ethyl acetate, butyl acetate;

aromatic hydrocarbons such as benzene, toluene;

aromatic heterocyclic compounds such as pyridine, lutidine;

amides such as N, N-dimethylformamide, N-methylpyrrolidone;

halogenated compounds such as chloroform, methylene chloride;

alcohols such as methanol, ethanol, 2-propanol, 2,2-dimethylethanol;

aliphatic hydrocarbon compounds such as hexane, heptane, petroleum ether;

carboxylic acids such as formic acid, acetic acid; and water.

[0364] In addition, the solvents used in the reaction can be used as a single solvent or as a mixture of two to 6 types of solvents.

[0365] In addition, the reaction may be carried out in the presence of amines such as triethylamine, N, N-diisopropylamine, pyridine, N-methylmorpholine or bases such as sodium hydroxide, potassium carbonate. Alternatively, the reaction may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid.

[0366] Compounds obtained by the above-mentioned methods: (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij) they can be isolated or purified by conventional separation methods, such as recrystallization, distillation, chromatography. If the compounds of the present invention: (Ie), (If), (Ih), (Ii) and (Ij) or comparative compounds (Ia), (Ib), (Ic), (Id) and (Ig) are obtained in free form, they can be converted to salts by known methods or by a comparable method (e.g. neutralization) or in the reverse situation, if they are obtained in the form of salts, they can be converted to the free form or other salts by by known methods or by a comparable method. If the compounds obtained are racemates, they can be separated into form d and form I using conventional optical resolution methods.

[0367] Compounds being raw materials for compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij) or salts are not particularly limited as long as this does not affect the reaction. Examples of such salts are the same as the salts of compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij).

[0368] In any of the above-mentioned production methods or processes, if desired, compound (Io) can be synthesized by the additional use of one or a combination of known reactions, such as protection / deprotection reactions, acylation reactions, alkylation reactions, hydrogenation reactions, oxidation reactions, reduction reactions, carbon chain extension reactions and substituent exchange reactions.

[0369] If the target products are obtained in the free form by the above-mentioned reactions, they can be converted to the corresponding salts by ordinary methods or if they are obtained in the form of salts, they can be converted to the free form or other salts by the means of ordinary ways. The obtained compound (Io) can be isolated from the reaction mixture and purified by known methods such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography.

[0370] If compound (Io) exists as a configuration isomer, diastereomer or conformer, if desired, it can be isolated by the isolation and purification methods mentioned above, respectively. If compound (Io) is present as a racemate, it may be separated into form d and form I by conventional optical resolution methods.

[0371] Compound (Io) can be used in the form of a prodrug. A prodrug of compound (Io) is a compound that is converted to compound (Io) by reaction using enzymes or gastric acid under in vivo physiological conditions. Namely, it includes a compound that is converted to compound (Io) by enzymatic oxidation, reduction and hydrolysis or a compound that is converted to compound (Io) by hydrolysis using stomach acid.

[0372] Prodrugs of compound (Io) include compounds in which the amino group in compound (Io) is acylated, alkylated, or phosphorylated (e.g. oxo-1,3-dioxolen-4-yl) methoxycarbonyl, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); the hydroxyl group in compound (Io) is acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group in compound (Io) is acetylated, palmitoylated, propanoylated, pivalylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated); the carboxyl group in compound (Io) is esterified or amidated (for example, the carboxyl group in compound (Io) is converted to ethyl, phenyl, carboxymethyl, dimethylaminomethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl, phthalidyl, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl, cyclohexyloxycarbonylethyl or methylamidated). These compounds can be prepared from compound (Io) by known methods. Prodrugs of compound (Io) can be converted to compound (Io) under physiological conditions as described in "Development of Drugs" Vol. 7 Molecular Design, published in 1990 by Hirokawa Shoten, pages 163 to 198.

[0373] The compounds of the present invention have excellent PDE10A inhibitory activity and are useful for the following diseases and symptoms in mammals (e.g. humans, cows, horses, dogs, cats, monkeys, mice, rats, in particular humans): psychotic disorders (e.g. short psychotic disorder, common psychotic disorder); psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids or phencyclidine; delusional disorder; anxiety disorder; movement disorder; mood disorder; major depressive disorder; major depressive disorder superimposed on a psychotic disorder including delusional disorder or schizophrenia;

major depressive episode of mild, moderate or severe type; episode with manic or mixed mood; episode with hypomanic mood; depressive episode with atypical features; depressive episode with melancholic features; depressive episode with catatonic features; mood episode with the beginning after delivery; depression after stroke; dysthymic disorder; minor depressive disorder; autism; drug addiction; neurodegenerative disorder; neurodegeneration associated with brain injury; stroke-related neurodegeneration; neurodegeneration associated with cerebral infarction; hypoglycemia induced neurodegeneration; neurodegeneration associated with epilepsy; neurodegeneration associated with neurotoxin intoxication; multi-system atrophy; Alzheimer's disease; dementia; multi-infarct dementia; alcohol dementia or other drug-related dementia;

dementia associated with intracranial tumors or brain trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS related dementia; fronto-temporal dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorder (e.g. reading disorder, math disorder or written disorder); attention deficit / hyperactivity disorder; age-related cognitive decline; premenstrual dysphoric disorder; postpsychotic depressive disorder in schizophrenia; bipolar disorder including bipolar I disorder and bipolar II disorder; cyclothymic disorder; Parkinson's disease; Huntington's disease; paranoia; schizophrenia (e.g. paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia); schizophrenia disorder; schizoaffective disorder of the delusional or depressive type; personality disorder of the paranoid type; schizoid type personality disorder; obesity; metabolic syndrome; insulin independent diabetes mellitus (NIDDM); glucose intolerance;

[0374] In particular, the compound of the present invention is useful for preventing or treating schizophrenia.

[0375] Because the compound of the present invention exhibits excellent metabolic stability, better therapeutic effects are expected against the above-mentioned diseases even at a low dose.

[0376] The compound of the present invention may be administered safely, as such, or in a dosage form that is prepared according to a method known per se for the preparation of pharmaceutical preparations (e.g. methods described in Japanese pharmacopoeia), such as tablets (including coated tablets sugar-coated tablets, film-coated tablets, sublingual tablets, disintegrating tablets and buccal tablets), pills, powders, granules, capsules (including soft capsules and microcapsules), lozenges, syrups, liquid dosage forms, emulsions, controlled release preparations (e.g. rapid release formulation, sustained release formulation, sustained release microcapsule), aerosols, films (e.g. films orally disintegrating adhesive films for use on the oral mucosa), injections (e.g. subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip, percutaneous absorbent, ointment, lotion, patch, suppositories (for example, rectal suppository, vaginal suppository), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, oral or parenteral (e.g. intravenous, intramuscular, subcutaneous, into the organ, into the nose, intradermal, eye dropping, into the brain, rectal, vaginal, intraperitoneal, directly to a pathological change).

[0377] Here, as organic pharmaceutically acceptable carriers, common organic or inorganic carrier substances are used as raw materials for the preparations. Carriers are added as carrier substances, lubricants, binders and disintegrants in solid preparations and as solubilizing agents, suspending agents, isotonic agents, buffers and soothing agents in liquid preparations. If desired, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can be used.

[0378] Preferred examples of carriers are: lactose, sucrose, D-mannitol, Dsorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, light silicic anhydride, and synthetic silicon anhydride metasilicon magnesium aluminate. [0379] Preferable examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.

[0380] Preferable examples of binders are the following: α-starch, sucrose, gelatin, acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxyethyl cellulose.

[0381] Preferable examples of disintegrants are: lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose

100 sodium, sodium carboxymethyl starch, light silicic anhydride and low-substituted hydroxypropyl cellulose.

[0382] Preferable examples of solvents are: water for injection, saline, Linger's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

[0383] Preferable examples of solubilizing agents are: polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

[0384] Preferable examples of suspending agents are: surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose; polysorbates and polyoxyethylene hardened castor oil.

[0385] Preferable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

[0386] Preferable examples of buffers include phosphate, acetate, carbonate and citrate buffer solutions.

[0387] Preferable examples of soothing agents include benzyl alcohol.

[0388] Preferable examples of antiseptics include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

[0389] Preferable examples of antioxidants include sulfites and ascorbates.

[0390] Preferable examples of coloring agents include water-soluble edible tar dyes (for example edible dyes such as Food Red No. 2 and No. 3), Yellow Food No. 4 and No. 5 (Food Yellow No. 4 and No. 5), blue food dye No. 1 and 2 (Food Blue No. 1 and 2)); water-insoluble organic pigments precipitated (e.g., aluminum salts of the above-mentioned water-soluble edible tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide).

[0391] Preferable examples of the sweeteners include sodium saccharin, dipotassium glycisinate, aspartame and stevia.

101 [0392] The therapeutic compositions of the present invention can be prepared by common methods in the field of formulation technology, for example, by the methods mentioned in Japanese Pharmacopoeia. Specific methods for preparing the formulations are described in detail below.

[0393] The content of the compound of the present invention in the therapeutic compositions of the present invention varies depending on the dosage form, dose of the compound of the present invention. For example, its content ranges from 0.01 to 100% by weight. and preferably from 0.1 to 95 wt. relative to the total amount of the composition.

[0394] The dose of the compound of the present invention depends on the injection destinations, routes of administration, target disease, symptoms. For example, for oral administration to patients with schizophrenia (adult, body weight about 60 kg), generally a single dose ranges from about 0.1 to 20 mg / kg body weight, preferably from about 0.2 to 10 mg / kg body weight, additionally preferably from about 0.5 to 10 mg / kg body weight, and this dose is preferably administered once a day or several times a day (e.g. 3 times).

[0395] The compounds may be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used to treat psychoses, in particular schizophrenia and bipolar disorder, obsessive compulsive disorder, major depression, Parkinson's disease, Alzheimer's disease, aggravation cognitive functions and / or memory loss, e.g., α7 nicotinic agonists, partial α7 nicotinic agonists, positive allosteric modulators of α7 nicotinic receptors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, calcium channel blockers, muscarinic m1 and m2 receptor modulators, adenosine receptor modulators, ampacin, glycine 1 transporter inhibitors, NMDA-R modulators, NMDA-R modulators, dopamine modulators, serotonin modulators, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, triple reuptake inhibitors, cannabinoid modulators and cholinesterase inhibitors (for example donepezil, rivastigmine and galantamine). In such combinations, all active ingredients can be administered either according to their usual dosage range or at a dose lower than their usual dosage range, and they can be administered either simultaneously or sequentially.

102 [0396] Drugs suitable for use in combination with the compounds of the present invention include, but are not limited to, other suitable drugs for the treatment of schizophrenia such as Haldol, Klozaril (Clozaril), Zyprexa, Risperdal, Abilify, Geodon, Invega and Serokwel (Seroquel) ; drugs for bipolar disorder, including but not limited to Lithium, Zyprexa, Abilify and Depakote; drugs for Parkinson's disease including, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Kemadrin, Artane and Kogentin (Cogentin); agents used to treat major depression, including, but not limited to, Elavil, Tofranil, Norpramin, Pamelor, Paxil, Prozac, Zoloft, Wellbutrin, Lexapro, Remeron, Effexor, Cymbalta; agents used in the treatment of Alzheimer's disease, including, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Clioquinol (Clioquinol); agents for the treatment of dementia, including, but not limited to, Mellaril, Haldol, Risperdal, Cognex, Aricept and Exelon; agents for the treatment of epilepsy, including, but not limited to, Dilanthin (Dilantin), Luminal, Tegretol, Depakote, Depakene, Zarontyna (Zarontin), Neurontin (Neurontin), Barbita, Solfeton and Felbatol; agents for treating multiple sclerosis, including but not limited to Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azathioprine (Azatioprine), Trexall and Kopakson (Copaxone); agents for the treatment of Huntington's disease, including, but not limited to, Elavil, Tofranil, Norpramin, Pamelor, Paxil, Prozac, Zoloft, Nitoman, Haldol, Thorazine (Thorazine), Mellaril, Dogmatil, Serokwel (Seroquel), Klozaril (Clozaril) and Risperdal; agents useful for treating diabetes, including, but not limited to, PPAR ligands (e.g., agonists, antagonists such as Rosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues (e.g., sulfonylureas, such as Glyburide, Glimepiride, Chlopropamide, and Tolbutamide and Glipizide and non-sulfonyl secretagogues), α-glucosidase inhibitors (such as Acarbose, Miglitol and Voglibose), insulin sensitizers (such as PPAR-γ agonists, for example glitazones; biguanides, PTP-1B inhibitors, DPPIV inhibitors and 11beta-HSD inhibitors), compounds that reduce hepatic glucose release (such as glucagon antagonists and metformin, e.g. Glucophag (Glucophage) and Glucophag XR (Glucophage XR)), insulin and insulin derivatives ( both long and short acting insulin forms and preparations); and anti-obesity drugs, including, but not limited to, β-3 agonists, CB-1 agonists, Y5 neuropeptide inhibitors, ciliary neurotrophic factor and derivatives (e.g. Axokine), appetite suppressants (e.g. Sibutramine) and lipase inhibitors (for example, orlistat).

103 [0397] The form of administration of concomitant drugs with a compound of the present invention is not particularly limited and is acceptable provided that the compound of the present invention is combined with concomitant drugs at the time of administration. Examples of such administration forms are as follows:

(1) Administration of a single preparation obtained by the simultaneous formulation of a compound of the present invention with an adjunct drug, (2) Simultaneous administration by means of the same route of administration of two types of preparations obtained by independent formulation of the compound of the present invention and an adjunct drug, (3) Administration at different times by the same route of administration of two types of preparations obtained by independently formulating the compound of the present invention and the associated drug, (4) Simultaneous administration by different routes of administration of two types of preparations obtained by independent formulation of the compound of the present invention and an accompanying medicine, (5) Administration at different times by different routes of administration of two types of formulations obtained by independently formulating the compound of the present invention and an adjunct drug. (For example, ordering the composition of the present invention and concomitant medication or administration in reverse order.) These administration forms are summarized below and given briefly as the combination agent of the present invention.

[0398] When the combination agent of the present invention is administered, the adjunct drug and the compound of the present invention may be administered at the same time, but the compound of the present invention may be administered after the administration of the accompanying drug or the adjunct drug may be administered after the administration of the compound of the present invention invention. When administered at different times, the time difference depends on the active ingredients administered, the form of the drugs and the methods of administration. For example, when the concomitant drug is administered first, the compound of the present invention can be administered over a period of 1 minute to 3 days, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour after administration of the accompanying compound. . However, if the compound of the present invention is administered first, the adjunct drug may be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours and more preferably 15 minutes to 1 hour after administration of the compound of the present invention.

104 [0399] If there are no problems with side effects of concomitant drugs, any dosage can be established. The daily dose of the concomitant medication depends on the doses, the patient being administered, routes of administration, target disease, and symptoms. For example, for oral administration to patients with schizophrenia (adult, body weight about 60 kg), the normal daily dose is in the range from about 0.1 to 20 mg / kg body weight, preferably from about 0.2 to 10 mg / kg body weight and more preferably from about 0.5 to 10 mg / kg body weight. It is preferred that this dose is administered once a day to several times a day (e.g. 3 times).

[0400] When a compound of the present invention is used in combination with an adjunct drug, the respective doses can be reduced to a safe range, taking into account the opposite effects of the respective drugs.

[0401] The combination agent of the present invention has low toxicity. For example, the compound of the present invention or / and the above-mentioned accompanying drug may be combined with a pharmaceutically acceptable carrier in accordance with a known method for the preparation of a therapeutic composition, such as tablets (including sugar-coated tablets and film-coated tablets), powder agents, granule agents , capsules (including soft capsules), liquids, injectable solutions, suppositories, long-term release agents. These compositions may be administered safely by oral or non-oral route (e.g., topical, rectal and intravenous routes). Pharmaceutically acceptable carriers that can be used to prepare the combination agent of the present invention can be the same as those used in the therapeutic composition according to the present invention as mentioned above.

[0403] The mixing ratio between a compound of the present invention and an adjunct drug in the combination agent of the present invention may be appropriately selected depending on the patient to whom it is administered, routes of administration and diseases.

[0404] The above-mentioned accompanying drugs can be combined in the correct proportion if two or more drugs are combined.

[0405] The dose of the concomitant drug may be appropriately selected based on the doses used clinically. In addition, the mixing ratio between the compound of the present invention and the accompanying drug may be appropriately selected depending on the patient to whom it is administered, routes of administration, target diseases, symptoms, combinations. For example, if the patient being treated is a human being,

105 the accompanying drug may be used in an amount ranging from 0.01 to 100 parts by weight with respect to 1 part by weight of the compound of the present invention.

[0406] For example, the content of a compound of the present invention in the combination agent of the present invention varies depending on the form of the preparations. Generally, it ranges from about 0.01 to 99.9% by weight, preferably from about 0.1 to 50% by weight. and more preferably from about 0.5 to 20 wt. in relation to the whole preparation.

[0407] The content of the accompanying drug in the combination agent of the present invention varies depending on the form of the preparations. Generally it ranges from about 0.01 to 99.9% by weight, preferably from about 0.1 to 50% by weight. and more preferably from about 0.5 to 20 wt. in relation to the whole preparation.

[0408] The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparations. It generally ranges from about 1 to 99.99 wt. and preferably from about 10 to 90% by weight in relation to the whole preparation.

[0409] When a compound of the present invention and an adjunct drug are formulated independently, the same contents may be used.

[0410] Because the doses may vary under different conditions, as mentioned above, doses lower than the above-mentioned doses may be sufficient, or doses exceeding the range may need to be administered.

Examples [0411] The present invention will be described below in detail with reference to reference examples, embodiments, preparation examples and experimental examples. Because these are simply examples, the present invention will not be limited to these examples and the present invention may be modified within the scope of the present invention.

[0412] In the following reference examples and embodiments, "room temperature" generally means a temperature of from about 10 ° C to 35 ° C. For%,% with respect to yield means% mol / mol,% with respect to the solvent used for chromatography means vol%. and% in other cases means wt. In the proton NMR spectrum, OH and NH protons that cannot be identified with

106 due to wide bands are not recorded in the data. Kiesselgel 60 from Merck &amp; Co., Inc. was used in silica gel chromatography, and Chromatorex NH from Fuji Silysia Chemical Ltd. was used in basic silica gel chromatography.

[0413] Abbreviations used in other parts of the text have the following meanings: s: singlet d: doublet dd: doublet doublet dt: doublet triplet t: triplet tt: triplet triplet td: triplet doublet q: quartet septet: septet m: multiplet br: wide

J: coupling constant

Hz: hertz

CDCl3: deuterated chloroform

DMSO-d6: deuterated dimethyl sulfoxide ¹H-NMR: proton nuclear magnetic resonance

HPLC: high performance liquid chromatography

THF: tetrahydrofuran

DMF: N, N-dimethylformamide

DMSO: dimethyl sulfoxide

NMP: N-methylpyrrolidone

HOBt: 1-hydroxybenzotriazole

WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate DMTMM: 4- (4,6-dimethoxy-1,3,5-triazine chloride hydrochloride) -2-yl) -4metylomorfoliniowego

DBU: 1,8-diazabicyclo [5.4.0] -7-undecene

LC-MS: liquid chromatography / mass spectroscopy

ESI: electrospray ionization

107

CDI: 1,1'-carbonyldiimidazole cares: dibenzylideneacetone

DIBAL: diisobutylaluminum hydride

DME: 1,2-dimethoxyethane

DPPA: diphenylphosphoryl azide

HMPA: hexamethylphosphoric triamide selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) bis (tetrafluoroborate)

TEA: triethylamine

TFA: trifluoroacetic acid

TMSCl: trimethylsilyl chloride

Xantphos: 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene

Rt: retention time [0414] All reagents and solvents were of commercial quality and were used without further purification. Column chromatography was carried out using 60 Merck silica gel (mesh size 230-400 mesh). Compounds and / or intermediates were purified by preparative high performance liquid chromatography (prep. HPLC) using the "a Gilson High through Put purification system" purification system.

[0415] Inverted YMC CombiPrep Pro C18, S-5 μm, 19 x 50 mm inverted phase systems. Gradient elution (flow rate 20 ml / min) was used, typically starting with 5% acetonitrile / 95% water and switching to 100% acetonitrile over a period of time of 7 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA).

[0416] Mass spectrometry analysis was performed according to liquid chromatography / mass spectroscopy (LCMS) methods. The method used a Waters LC-MS system (Agilent HP 1100 HPLC and a Micromass ZMD mass spectrometer for the LCMS, CAPCELL PAK C18, UG120, S-3 μm, 1.5 x35 mm for the chromatographic column, and the solvent system was 5-95% acetonitrile in water gradient with 0.04% TFA over a period of 3.60 minutes (flow rate 0.5 ml / min molecular weight range 200-800; coil voltage 20 V; column temperature 40 ° C). All masses are shown as protonated parent ions.

108

Reference example 1

3 - {[3- (Trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione [0417] ο ο

Me V Wie

<img file="PL2393360T3_D0017.tif" />

[0418] 3- (Trifluoromethyl) aniline (34.6 g, 215 mmol) was dissolved in a mixture of concentrated hydrochloric acid (64 ml) and water (64 ml). To the resulting mixture, a solution of sodium nitrate (16.6 g, 240 mmol) in water (100 mL) was added dropwise at 0 ° C. The mixture was stirred for 1 hour at 0 ° C. To the resulting diazonium salt solution, a solution of pentane-2,4-dione (22.0 g, 220 mmol) and sodium acetate (52.5 g, 640 mmol in ethanol (225 mL) and water (80 mL) was added dropwise at room temperature The mixture was stirred for 18 hours at room temperature with a mechanical stirrer. The orange precipitate was filtered off and washed with water (150 ml x 3), 50 percent aqueous ethanol (100 ml x 2) and n-hexane (100 ml) and then dried under vacuum at 50 ° C for 5 hours to obtain 52, 7 g (90%) 3 - {[3- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione as an orange solid.

[0419] ¹H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 3H), 2.63 (s, 3H), 7.45-7.44 (m, 1H), 7.58-7.51 ( m, 2H), 7.66 (s, 1H), 14.68 (s, 1H). LC-MS (MH⁺) 273,10.

Reference example 2

3- [3- (Dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0420]

Ο Ο

<img file="PL2393360T3_D0018.tif" />

[0421] A mixture of 3 - {[3- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (4.3 g, 15.8 mmol) and N, N-dimethylformamide dimethyl acetal (40 ml) was heated in a bath oil at 120 ° C for 5 hours. The solvent was removed under reduced pressure to give a quantitative yield of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as

109 black oil which was used as such in the next step without further purification.

[0422] LC-MS (MH⁺) 338,16.

Reference example 3

3 - {[4- (Trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione [0423] ο ο

MsAAms

L |. | -N

HN

Φ cf₃ [0424] To a solution of 4- (trifluoromethyl) aniline (1090 mg, 6.80 mmol) in 5 ml of water and 5 ml of concentrated hydrochloride solution, sodium (III) nitrate (563 mg, 8.16) was added dropwise at 0 ° C mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. Then, a solution of sodium acetate (1670 mg, 20.40 mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 ml ethanol and 6 ml water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - {[4- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (580 mg, 31%).

[0425] ¹H NMR (300 MHz, CDCl3): δ 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), 14.59 (s, 1H).

Reference example 4

3- [3- (Dimethylamino) prop-2-enoyl] -1- [4- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0426]

<img file="PL2393360T3_D0019.tif" />

[0427] 3 - {[4- (Trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (580 mg, 2.13 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3110 (dimethylamino) prop-2-enoyl] -1- [4- (trifluoromethyl) phenyl] pyridazine-4 (1H) - one which was used in the next step without further purification.

Reference example 5

3 - [(3-Chlorophenyl) hydrazone] pentane-2,4-dione [0428] ο ο ην ·^ν [0429] To a solution of 3-chloroaniline (1000 mg, 7.87 mmol) in 5 ml of water and 5 ml of concentrated hydrochloride solution, sodium (III) nitrate (652 mg, 9.45 mmol) was added dropwise at 0 ° C. in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (866 mg, 8.66 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(3-chlorophenyl) hydrazone] pentane-2,4-dione (450 mg, 24% ).

[0430] LCMS: m / z = 239 [35Cl, M⁺+ H].

Reference example 6

1- (3-Chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one [0431]

<img file="PL2393360T3_D0020.tif" />

[0432] 3 - [(3-Chlorophenyl) hydrazono] pentane-2,4-dione (450 mg, 1.89 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- (3-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without additional purification.

111

Reference example 7

3 - [(2-Methoxyphenyl) hydrazone] pentane-2,4-dione [0433]

<img file="PL2393360T3_D0021.tif" />

[0434] To a solution of 2-methoxyaniline (1000 mg, 8.13 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (673 mg, 9.76 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for an hour. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(2-methoxyphenyl) hydrazone] pentane-2,4-dione (1500 mg, 79% ).

[0435] LCMS: m / z = 235 [M⁺+ H].

Reference example 8

- [3- (Dimethylamino) prop-2-enoyl] -1- (2-methoxyphenyl) pyridazin-4 (1H) -one [0436]

Me

Me [0437] 3 - [(2-Methoxyphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.14 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under reflux at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-methoxyphenyl) pyridazine-4 (1H) -one, used in the next stage without additional purification.

which

Reference example 9

3 - [(4-Methoxyphenyl) hydrazone] pentane-2,4-dione [0438]

112

<img file="PL2393360T3_D0022.tif" />

[0439] To a solution of 4-methoxyaniline (1000 mg, 8.13 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium nitrate (III) nitrate (673 mg, 9.76 mmol) was added dropwise at 0 ° C. in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(4-methoxyphenyl) hydrazone] pentane-2,4-dione (950 mg, 50% ).

[0440] ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 3H), 2.62 (s, 3H), 3.86 (s, 3H), 6.966.98 (m, 2H), 7.38 -7.41 (m, 2H), 14.99 (s, 1H).

Reference example 10

3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-methoxyphenyl) pyridazin-4 (1H) -one [0441]

<img file="PL2393360T3_D0023.tif" />

[0442] 3 - [(4-Methoxyphenyl) hydrazone] pentane-2,4-dione (500 mg, 2.14 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-methoxyphenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 11

3 - [(3-Fluorophenyl) hydrazono] pentane-2,4-dione [0443]

<img file="PL2393360T3_D0024.tif" />

113 [0444] To a solution of 3-fluoroaniline (1000 mg, 9.00 mmol) in 5 ml of water and 5 ml of concentrated hydrochloride solution, sodium (III) nitrate (746 mg, 10.80 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane, and dried to give 3 - [(3-fluorophenyl) hydrazone] pentane-2,4-dione (650 mg, 33% ).

[0445] ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 3H), 2.62 (s, 3H), 6.90 (dt, J = 2.4, 8.0 Hz, 1H), 7 , 11 (dd, J = 1.6, 8.0 Hz, 1H), 7.21 (td, J = 2.4, 10.0 Hz, 1H), 7.34-7.39 (m, 1H ), 14.61 (s, 1H).

Reference example 12

3- [3- (Dimethylamino) prop-2-enoyl] -1- (3-fluorophenyl) pyridazin-4 (1H) -one [0446]

<img file="PL2393360T3_D0025.tif" />

[0447] 3 - [(3-Fluorophenyl) hydrazono] pentane-2,4-dione (650 mg, 2.93 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-fluorophenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 13

3 - [(2-Fluorophenyl) hydrazone] pentane-2,4-dione [0448] ο ο

Me Ύ Me

<img file="PL2393360T3_D0026.tif" />

[0449] To a solution of 2-fluoroaniline (1000 mg, 9.00 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (746 mg, 10.80 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C

114 for 1 hour. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane, and dried to give 3 - [(2-fluorophenyl) hydrazone] pentane-2,4-dione (1280 mg, 64 %).

[0450] ¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.62 (s, 3H), 7.14-7.24 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 14.71 (s, 1H).

Reference example 14

3- [3- (Dimethylamino) prop-2-enoyl] -1- (2-fluorophenyl) pyridazin-4 (1H) -one [0451]

<img file="PL2393360T3_D0027.tif" />

[0452] 3 - [(2-Fluorophenyl) hydrazono] pentane-2,4-dione (600 mg, 2.70 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-fluorophenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 15

3 - [(4-Fluorophenyl) hydrazone] pentane-2,4-dione [0453]

<img file="PL2393360T3_D0028.tif" />

[0454] To a solution of 4-fluoroaniline (1000 mg, 9.00 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (746 mg, 10.80 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered,

115 washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(4-fluorophenyl) hydrazone] pentane-2,4-dione (1200 mg, 60%).

[0455] ¹H NMR (300 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.61 (s, 3H), 7.09-7.15 (m, 2H), 7.37-7.41 ( m, 2H), 14.85 (s, 1H).

Reference example 16

- [3- (Dimethylamino) prop-2-enoyl] -1- (4-fluorophenyl) pyridazin-4 (H) -one [0456] ο ο [Λ / ν'τΒ¹⁶

Β, .Ν Κ Me Ν

<img file="PL2393360T3_D0029.tif" />

F [0457] 3 - [(4-Fluorophenyl) hydrazono] pentane-2,4-dione (650 mg, 2.93 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a reflux condenser at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-fluorophenyl) pyridazin-4 (1H) -one next step without additional purification.

Reference example 17

3 - [(4-Chloro-phenyl)-hydrazono] pentane-2,4-dione [0458]

<img file="PL2393360T3_D0030.tif" />

CI [0459] 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 (III) nitrate (652 mg, 9.45 mmol) was added dropwise at 0 ° C ) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (1023 mg, 10.23 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(4-chlorophenyl) hydrazono] pentane-2,4-dione (1680 mg, 90% ).

116 [0460] ¹H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.61 (s, 3H), 7.33-7.39 (m, 4H), 14.70 (s, 1H) .

Reference example 18

1- (4-Chloro-phenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one [0461]

<img file="PL2393360T3_D0031.tif" />

Cl [0462] 3 - [(4-Chlorophenyl) hydrazono] pentane-2,4-dione (600 mg, 2.52 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under reflux at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- (4-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 19

3 - [(2-Methylphenyl) hydrazone] pentane-2,4-dione [0463]

<img file="PL2393360T3_D0032.tif" />

[0464] To a solution of 2-methylaniline (1000 mg, 9.34 mmol) in 10 ml of acetic acid and 2 ml of concentrated hydrochloride solution, sodium (III) nitrate (774 mg, 11.21 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(2-methylphenyl) hydrazone] pentane-2,4-dione (1000 mg, 49% ).

LCMS: m / z = 219 [M⁺+ H].

117

Reference example 20

3- [3- (Dimethylamino) prop-2-enoyl] -1- (2-methylphenyl) pyridazin-4 (1H) -one [0465] ο ο

<img file="PL2393360T3_D0033.tif" />

[0466] 3 - [(2-Methylphenyl) hydrazono] pentane-2,4-dione (1000 mg, 4.59 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-methylphenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 21

3 - [(3-Methylphenyl) hydrazono] pentane-2,4-dione [0467]

Ν

ΗΝ '[0468] To a solution of 3-methylaniline (1000 mg, 9.34 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21) was added dropwise at 0 ° C mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(3-methylphenyl) hydrazono] pentane-2,4-dione (500 mg, yield 24 %). LCMS: m / z = 219 [M⁺+ H].

Reference example 22

3- [3- (Dimethylamino) prop-2-enoyl] -1- (3-methylphenyl) pyridazin-4 (1H) -one [0469]

118

<img file="PL2393360T3_D0034.tif" />

[0470] 3 - [(3-Methylphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.29 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-methylphenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

Reference example 23

3 - [(3-Methoxyphenyl) hydrazone] pentane-2,4-dione [0471]

<img file="PL2393360T3_D0035.tif" />

[0472] To a solution of 3-methoxyaniline (1000 mg, 8.13 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (673 mg, 9.76 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(3-methoxyphenyl) hydrazone] pentane-2,4-dione (840 mg, 44% ). LCMS: m / z = 235 [M⁺+ H].

Reference example 24

3- [3- (Dimethylamino) prop-2-enoyl] -1- (3-methoxyphenyl) pyridazin-4 (1H) -one [0473]

<img file="PL2393360T3_D0036.tif" />

[0474] 3 - [(3-Methoxyphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.14 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and

119 the mixture was heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-methoxyphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 25

- {[2- (Trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione [0475] ο ο

Ν

ΗΝ ^Ρ'° Ό [0476] To a solution of 2- (trifluoromethyl) aniline (1.09 g, 6.80 mmol) in 5 ml water and 5 ml concentrated hydrochloride solution, sodium (III) nitrate (563) was added dropwise at 0 ° C mg, 8.16 mmol) in 4 mL water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1.67 g, 20.40 mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 ml of ethanol and 6 ml of water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - {[2- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (634 mg, 33%).

[0477] ¹H NMR (300 MHz, CDCl3): δ 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 Hz, 1H), 15.06 (s, 1H).

Reference example 26

3- [3- (Dimethylamino) prop-2-enoyl] -1- [2- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0478]

<img file="PL2393360T3_D0037.tif" />

[0479] 3 - {[2- (Trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (634 mg, 2.33 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3120 (dimethylamino) prop-2-enoyl] -1- [2- (trifluoromethyl) phenyl] pyridazine-4 (1H) - one which was used in the next step without further purification.

Reference example 27

3 - [(4-Morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione [0480]

<img file="PL2393360T3_D0038.tif" />

[0481] To a solution of 4-morpholin-4-ylaniline (1000 mg, 5.62 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (465 mg, 6) was added dropwise at 0 ° C. , 74 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane, and dried to give 3 - [(4-morpholin-4-ylphenyl) hydrazone] pentane-2,4-dione (900 mg, 55%). [0482] LCMS: m / z = 290 [M⁺+ H].

Reference example 28

3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-morpholin-4-ylphenyl) pyridazin-4 (1H) -one [0483]

<img file="PL2393360T3_D0039.tif" />

[0484] 3 - [(4-Morpholin-4-ylphenyl) hydrazone] pentane-2,4-dione (900 mg, 3.11 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-morpholin-4-ylphenyl) pyridazine-4 (1H ) -one which was used in the next step without further purification.

121

Reference example 29

3- (Phenylhydrazone) pentane-2,4-dione [0485] ο ο

MeAAwie

<img file="PL2393360T3_D0040.tif" />

[0486] To a solution of aniline (2000 mg, 21.50 mmol) in 30 ml acetic acid and 5 ml concentrated hydrochloride solution, sodium (III) nitrate (1780 mg, 25.80 mmol) in 8 was added dropwise at 0 ° C ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (5290 mg, 64.50 mmol) and acetylacetone (2795 mg, 27.95 mmol) in 20 mL ethanol and 12 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3- (phenylhydrazone) pentane-2,4-dione (2955 mg, 67%).

[0487] ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 3H), 2.61 (s, 3H), 7.21 (dd, J = 8.0,

4.4 Hz, 1H), 7.41 (d, J = 4.4 Hz, 4H), 14.74 (s, 1H).

Reference example 30

3- [3- (Dimethylamino) prop-2-enoyl] -1-phenylpyridazin-4 (1H) -one [0488]

<img file="PL2393360T3_D0041.tif" />

[0489] 3- (Phenylhydrazone) pentane-2,4-dione (470 mg, 2.30 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was refluxed at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1-phenylpyridazin-4 (1H) -one, which was used in the next step without further purification.

[0490] ¹H NMR crude product (400 MHz, DMSO-d6): δ ppm 2.84 (s, 3H), 3.11 (s, 3H), 5.50 (br, 1H), 6.55 (d, J = 8.0 Hz, 1H), 7.43-7.46 (m, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 8.81 (d, J = 8.0 Hz, 1H).

122

Reference example 31

3 - [(4-Methylphenyl) hydrazono] pentane-2,4-dione [0491]

<img file="PL2393360T3_D0042.tif" />

[0492] To a solution of 4-methylaniline (1000 mg, 9.34 mmol) in 10 ml of acetic acid and 2 ml of concentrated hydrochloride solution, sodium (III) nitrate (774 mg, 11.21 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(4-methylphenyl) hydrazone] pentane-2,4-dione (480 mg, 24% ).

[0493] ¹H NMR (400 MHz, CDCl3): δ ppm 2.36 (s, 3H), 2.49 (s, 3H), 2.60 (s, 3H), 7.21 (d, J = 8.0 Hz , 2H), 7.32 (d, J = 8.0 Hz, 2H), 14.82 (s, 1H).

Reference example 32

3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-methylphenyl) pyridazin-4 (1H) -one [0494]

<img file="PL2393360T3_D0043.tif" />

[0495] 3 - [(4-Methylphenyl) hydrazono] pentane-2,4-dione (462 mg, 2.12 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-methylphenyl) pyridazin-4 (1H) -one, which was used in the next stage without additional purification.

[0496] ¹H NMR crude product (400 MHz, DMSO-d6): δ 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), 8.76 (d, J = 8, 0 Hz, 1H).

123

Reference example 33

3 - {[2- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione [0497]

<img file="PL2393360T3_D0044.tif" />

[0498] To a solution of 2- (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 15 ml acetic acid and 2.5 ml concentrated hydrochloride solution, sodium nitrate (III) (518 mg) was added dropwise at 0 ° C. 7.50 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - {[2- (difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione ( 1590 mg, 94%).

[0499] LCMS: m / z = 271 [M⁺+ H].

Reference example 34

1- [2- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) on [0500]

<img file="PL2393360T3_D0045.tif" />

[0501] 3 - {[2- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione (500 mg, 1.85 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- [2 (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazine-4 (1H) - one which was used in the next step without further purification.

Reference example 35

3- {[3- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione

124 [0502]

<img file="PL2393360T3_D0046.tif" />

[0503] To a solution of 3- (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 10 ml of acetic acid and 2 ml of concentrated hydrochloride solution, sodium (III) nitrate (518 mg, 7) was added dropwise at 0 ° C. 50 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - {[3- (difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione ( 1500 mg, 89%).

[0504] LCMS: m / z = 271 [M⁺+ H].

Reference example 36

1- [3- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) on [0505] ο ο

<img file="PL2393360T3_D0047.tif" />

[0506] 3 - {[3- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione (800 mg, 2.96 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- [3- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazine-4 (1H) - one which was used in the next step without further purification.

Reference example 37

- {[4- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione [0507]

125

<img file="PL2393360T3_D0048.tif" />

[0508] To a solution of 4- (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 10 ml of acetic acid and 2 ml of concentrated hydrochloride solution, sodium (III) nitrate (518 mg, 7) was added dropwise at 0 ° C. 50 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - {[4- (difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione ( 1400 mg, 82% yield).

[0509] LCMS: m / z = 271 [M⁺+ H].

Reference example 38

1- [4- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) on [0510]

<img file="PL2393360T3_D0049.tif" />

[0511] 3 - {[4- (Difluoromethoxy) phenyl] hydrazone} pentane-2,4-dione (600 mg, 2.22 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- [4- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazine-4 (1H) - one which was used in the next step without further purification.

Reference example 39

3 - [(2-Morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione [0512]

126

<img file="PL2393360T3_D0050.tif" />

[0513] To a solution of 2-morpholin-4-yaniline (1000 mg, 5.62 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (465 mg, 6) was added dropwise at 0 ° C , 74 mmol) in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(2-morpholin-4-ylphenyl) hydrazone] pentane-2,4-dione (1000 mg, 62%). [0514] LCMS: m / z = 290 [M⁺+ H].

Reference example 40

3- [3- (Dimethylamino) prop-2-enoyl] -1- (2-morpholin-4-ylphenyl) pyridazin-4 (1H) -one [0515]

<img file="PL2393360T3_D0051.tif" />

[0516] 3 - [(2-Morpholin-4-ylphenyl) hydrazone] pentane-2,4-dione (1000 mg, 2.46 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-morpholin-4-ylphenyl) pyridazine-4 (1H ) -one which was used in the next step without further purification.

Reference example 41

3- (Pyridin-3-ylhydrazone) pentane-2,4-dione [0517]

Me

<img file="PL2393360T3_D0052.tif" />

127 [0518] To 3-aminopyridine (564 mg, 6.00 mmol) was added 4 mL concentrated sulfuric acid and 1.2 mL water at 0 ° C and the mixture was stirred at room temperature until it became clear. A solution of sodium nitrate (414 mg, 6.00 mmol) in water (1.2 mL) was added to the reaction mixture at 0 ° C. The mixture was stirred for several minutes (&gt; 15 min). The diazonium salt solution was poured into a solution of 2,4-pentanedione (600 mg, 6.00 mmol) and potassium acetate (18.0 g, 180 mmol) in ethanol (120 mL) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 30 minutes. The reaction mixture was added to 120 mL saturated aqueous Na2CO3 solution. The mixture was extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3- (pyridin-3-ylhydrazone) pentane-2,4-dione (242 mg, 20% yield).

[0519] LCMS: m / z = 206 [M⁺+ H].

Reference example 42

3- [3- (Dimethylamino) prop-2-enoyl] -1-pyridin-3-yl-pyridazin-4 (1H) -one [0520]

<img file="PL2393360T3_D0053.tif" />

[0521] 3- (Pyridin-3-ylhydrazone) pentane-2,4-dione (200 mg, 0.98 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated to reflux. at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1-pyridin-3-yl-pyridazin-4 (1H) -one, which was used in the next step without additional purification.

[0522] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 2.90 (s, 3H), 3.15 (s, 3H),

5.64 (d, J = 11.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 7.45-7.48 (m, 1H), 8.00-8 , 03 (m, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.65-8.66 (m, 1H), 8.88 (d, J = 2.8 Hz, 1H).

Reference example 43

3- (Pyridin-4-ylhydrazone) pentane-2,4-dione [0523]

128

<img file="PL2393360T3_D0054.tif" />

[0524] 4-Aminopyridine (470 mg, 5.00 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature, it was cooled to -6 ° C and solid sodium (III) nitrate (350 mg, 5.00 mmol) was added over 10 minutes. Small pieces of ice (50 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2.4pentanedione (500 mg, 5.00 mmol) and potassium acetate (20 g) in ethanol (250 ml). The solution was stirred for 15 minutes, added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3- (pyridin-4-ylhydrazone) pentane-2.4 -dione (149 mg, 14% yield).

[0525] ¹H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 3H), 2.62 (s, 3H), 7.27-7.29 (m, 2H),

8.59-8.61 (m, 2H), 14.23 (s, 1H).

Reference example 44

3- [3- (Dimethylamino) prop-2-enoyl] -1-pyridin-4-yl-pyridazin-4 (1H) -one [0526]

<img file="PL2393360T3_D0055.tif" />

[0527] 3- (Pyridin-4-ylhydrazone) pentane-2,4-dione (120 mg, 0.58 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated to reflux. at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1-pyridin-4-yl-pyridazin-4 (1H) -one, which was used in the next step without additional purification.

[0528] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 2.92 (s, 3H), 3.16 (s, 3H), 5.56-5.58 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 4.8, 1.6 Hz, 2H), 8.30 (d, J = 8.0 Hz, 1H), 8.74 ( dd, J = 4.8, 1.6 Hz, 2H).

129

Reference example 45

3 - [(2-Chloro-phenyl)-hydrazono] pentane-2,4-dione [0529]

<img file="PL2393360T3_D0056.tif" />

[0530] To a solution of 2-chloroaniline (1000 mg, 7.87 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium (III) nitrate (652 mg, 9.45 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (1940 mg, 23.62 mmol) and acetylacetone (1024 mg, 10.24 mmol) in 10 mL ethanol and 6 mL water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(2-chlorophenyl) hydrazono] pentane-2,4-dione (860 mg, 46% ).

[0531] ¹H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 3H), 2.64 (s, 3H), 7.11-7.15 (m, 1H), 7.34-7.37 ( m, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (dd, J = 8.0, 1.2 Hz, 1H), 14.88 (s , 1H).

Reference example 46

1- (2-Chloro-phenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one [0532]

<img file="PL2393360T3_D0057.tif" />

[0533] 3 - [(2-Chlorophenyl) hydrazono] pentane-2,4-dione (500 mg, 2.10 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- (2-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without additional purification.

[0534] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 2.90 (s, 3H), 3.12 (s, 3H), 5.56-5.59 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 7.42-7.45 (m, 2H), 7.52-7.57 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H ).

130

Reference example 47

3 - {[3- (Methylsulfanyl) phenyl] hydrazono} pentane-2,4-dione [0535]

<img file="PL2393360T3_D0058.tif" />

[0536] 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 dropwise with sodium nitrate solution (8.38 g) , 121 mmol) in water (25 ml) maintaining the temperature between -5 ° C and 5 ° C. The in-situ diazonium solution was quickly added to a mixture of 2,4-pentanedione (10.2 g, 102 mmol) and sodium acetate (150 g, 183 mmol) in ethanol (170 mL) and water (60 mL) cooled to less than 0 ° C. After stirring at 0 ° C for 30 minutes, the suspension was filtered, washed with water (40 ml) and evaporated with toluene to give 3 - {[3- (methylsulfanyl) phenyl] hydrazone} pentane-2,4-dione (23, 10 g, 92%) as a yellow-red solid.

[0537] ¹H NMR (500 MHz, DMSO-d6) δ 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 (br s, 1H); APCI MS m / z 251 [M + H]⁺.

Reference example 48

3- [3- (Dimethylamino) prop-2-enoyl] -1- [3- (methylsulfanyl) phenyl] pyridazin-4 (1H) on [0538]

<img file="PL2393360T3_D0059.tif" />

[0539] A mixture of 3 - {[3- (methylsulfanyl) phenyl] hydrazone} pentane-2,4-dione (14.9 g, 59.6 mmol) in N, N-dimethylformamide dimethyl acetal (70 mL) was stirred at 125 ° C for 2.5 hours. After this time, the reaction mixture was directly concentrated and then dissolved in methanol (80.0 mL). After concentration, the crude product was purified by flash chromatography (silica gel, methylene chloride to 95: 5 methylene chloride / methanol) to give 3- [3- (dimethylamino) prop-2-enoyl] -1131 [3- (methylsulfanyl) ) phenyl] pyridazine-4 (1H) -one (16.3 g, 87%) as a yellow-brown solid.

[0540] ¹H NMR (500 MHz, DMSO-d6) δ 2.54 (s, 3H), 2.83 (s, 3H), 3.09 (s, 3H), 5.23 (br s, 1H), 6, 53 (d, J = 8.0 Hz, 1H), 7.29-7.32 (m, 1H), 7.43-7.53 (m, 4H), 8.81 (d, J = 8, 0 Hz, 1H); APCI MS m / z 316 [M + H]⁺.

Reference example 49

1- [3- (Methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one and 1- [3- (methylsulfanyl) phenyl] -3- (1- phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) -one [0541]

<img file="PL2393360T3_D0060.tif" />

[0542] A mixture of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (methylsulfanyl) phenyl] pyridazin-4 (1H) -one (3.69 g, 11.7 mmol) in methanol ( 80 ml) was treated with phenylhydrazine (2.66 g, 24.6 mmol) and the resulting mixture was stirred at reflux for 8 hours. After this time, the reaction mixture was directly concentrated to remove methanol and then dissolved in methylene chloride (100 mL). The solution was washed with 2 N 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) to give 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol5 -yl) pyridazin-4 (1H) -one and 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) -one (2.72 g, 65%) in a regiomeric ratio of about 1: 1 as a white solid.

[0543] ¹H NMR for 2 isomers (500 MHz, DMSO-d6) δ 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, 1H), 7, 34-7.39 (m, 5H), 7.42 (d, J = 7.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.50-7.56 (m, 3H), 7.59 (d, J = 9.3 Hz, 1H), 7.68 (s, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 2H), 8.59 (d, J = 2.4 Hz, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 7.9 Hz, 1H); APCI MS m / z 361 [M + H]⁺.

132

Reference example 50

- [(3-Hydroxyphenyl) hydrazone] pentane-2,4-dione [0544]

<img file="PL2393360T3_D0061.tif" />

[0545] A solution of 3-aminophenol (5.16 g, 47.3 mmol) in tetrafluoroboric acid (30 mL, 50% in water) was cooled using an ice-brine bath and treated with a drop of sodium nitrate (III) 92 g, 56.8 mmol) in water (18 ml) maintaining the bath temperature between -5 ° C and 5 ° C. The in-situ diazonium solution was quickly added to a mixture of 2,4-pentanedione (4.73 g, 47.3 mmol) and sodium acetate (100 g, 73.5 mmol) in ethanol (80 mL) and water (30 mL) in temperature below 0 ° C. After stirring at 0 ° C for 30 minutes, the suspension was filtered, washed with water (70 ml) and evaporated with toluene to give 3 - [(3-hydroxyphenyl) hydrazone] pentane-2,4-dione (5.85 g, 56 %) as a brick solid.

[0546] ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.42 (s, 6H), 3.44 (br s, 1H), 6.58-6.60 (m, 1H), 6.90-6, 93 (m, 1H), 6.99 (d, J = 2.1 Hz, 1H), 7.15-7.18 (m, 1H); ESI MS m / z 221 [M + H]⁺.

Reference example 51

3- [3- (Dimethylamino) prop-2-enoyl] -1- (3-hydroxyphenyl) pyridazin-4 (1H) -one [0547]

<img file="PL2393360T3_D0062.tif" />

[0548] A mixture of 3 - [(3-hydroxyphenyl) hydrazone] pentane-2,4-dione (2.02 g, 9.18 mmol) in N, N-dimethylformamide dimethyl acetal (20 mL) was stirred at 100 ° C for 1 hour. After this time, the reaction mixture was directly concentrated and then dissolved in methanol (60 mL). After evaporation by silica gel, the crude product was purified by flash chromatography (silica gel, methylene chloride to 92: 8 methylene chloride / methanol) to give 3- [3- (dimethylamino) prop-2-enoyl] -1- ( 3-hydroxyphenyl) pyridazine-4 (1H) -one (1.72 g, 66%) as a brown-red solid.

133 [0549] ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.83 (s, 3H), 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) , 8.74 (d, J = 8.0 Hz, 1H), 9.93 (s, 1H); ESI MS m / z 286 [M + H]⁺.

Reference example 52

1- (3-Hydroxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [0550]

<img file="PL2393360T3_D0063.tif" />

[0551] A mixture of 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-hydroxyphenyl) pyridazin 4 (1H) -one (0.481 g, 1.69 mmol) in methanol (10 mL) was treated with phenylhydrazine (0.462 g, 4.28 mmol) and the resulting mixture was stirred at reflux for 14 hours. After this time, the reaction mixture was directly concentrated to remove methanol and then dissolved in methylene chloride (60 mL). The solution was washed with water (60 ml) and brine (20 ml). After concentration with silica gel, chromatography (silica, methylene chloride to 1:19 methanol / methylene chloride) gave 1- (3-hydroxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on (0.360 g, 65%) as a brown-yellow solid.

[0552] ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.63 (d, 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), 8 , 59 (d, J = 2.3 Hz, 1H), 8.81 (d, J = 7.8 Hz, 1H), 10.0 (s, 1H); ESI MS 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-phenyl1H-pyrazol-3-yl) -1- (3 -sulfanylphenyl) pyridazine-4 (1H) -one [0553]

<img file="PL2393360T3_D0064.tif" />

[0554] A solution of 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin (1H) -one and 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) 134one (0.300 g, 0.83 mmol) and sodium t-butylthiolate (0.295 g, 2.63 mmol) in DMF (6 mL) heated at 170 ° C in a sealed tube for 2.5 days. After this time, the reaction mixture was cooled to room temperature and diluted with water (60 mL). Aqueous HCl (1 N, 2 mL, 2 mmol) was added and the reaction mixture was extracted with ethyl acetate (2 → 80 mL). The combined organic phases were washed with an aqueous 5% LiCl solution (100 ml) and saturated aqueous NaCl solution (80 ml). The organic phases were dried (MgSO4) and concentrated to give a mixture of the title compounds as a brown gum (0.325 g). LCMS analysis of the reaction product showed that 2 isomers of the thiol product were prepared in a ratio of ~ 1.5: 1. The crude product was used in the following reaction without further purification or characterization.

Reference example 54

1- [3- (1H-Benzimidazol-2-ylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin 4 (1H) -one and 1- [3- (1H-benzimidazol-2 -ilosulfanylo) phenyl] -3- (1-phenyl-1H-pyrazol-3-

<img file="PL2393360T3_D0065.tif" />

[0556] Solution of a 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- (3sulfanylphenyl) pyridazin-4 (1H) -one (0.325 g, 0.94 mmol), 2-chlorobenzimidazole (0.195 g, 1.27 mmol) and potassium carbonate (0.234 g, 1.70 mmol) in N-methylpyrrolidone (8.0 mL) was heated at 170 ° C in a sealed tube for 24 hours. After this time, the reaction mixture was cooled to room temperature and diluted with water (50 mL). Aqueous HCl (2 N, 0.800 mL, 1.60 mmol) was added and the reaction mixture was extracted with ethyl acetate (3 χ 60 mL). The combined organic phases were washed with an aqueous 5% LiCl solution (100 ml) and saturated aqueous NaCl solution (100 ml). The organics were dried (MgSO 4) and concentrated to a brown solid (0.312 g). The crude product was used in the following reaction without further purification or characterization.

135

Reference example 55

Methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazone} butanoate [0557]

<img file="PL2393360T3_D0066.tif" />

[0558] A suspension of 3- (trifluoromethyl) aniline (16.12 g, 100 mmol) in 6 N HCl (100 mL) was cooled to 0 ° C and treated dropwise with a sodium nitrate solution (8.33 g, 121 mmol) in water (20 ml). The resulting pale yellow solution was poured into a suspension 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 suspension was stirred for 10 minutes. After this 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 4). The product crystallized during concentration of ethyl acetate to obtain 19.997 g (69%) of methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazono} butanoate as pale yellow crystals.

[0559] ¹H NMR (300 MHz, CDCl3) shows a mixture of isomers. Main isomer δ ppm 2.62 (s, 3H), 3.90 (s, 3H), 7.37-7.45 (m, 1H), 7.46-7.54 (m, 1H), 7, 58 (s, 1H), 7.67 (s, 1H), 14.76 (br s, 1H); Secondary isomer δ ppm 2.52 (s, 3H), 3.93 (s, 3H), 7.37-7.45 (m, 1H), 7.46-7.54 (m, 2H), 7, 56 (s, 1H), 12.81 (br s, 1H); APCI MS m / z 289 [C12H11F3N2O3 + H]⁺.

Reference example 56

Methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate [0560] ο ο

<img file="PL2393360T3_D0067.tif" />

[0561] A solution of methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazone} butanoate (15.20 g, 52.7 mmol) in N, N-dimethylformamide dimethyl acetal (150 ml) was heated at reflux temperature for 2 hours. After this time, the reaction mixture was cooled to room temperature and then in an ice-water bath. Product collected for

136 by filtration to obtain methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (13.7 g, 87%) as pale yellow crystals. [0562]¹H NMR (300 MHz, CDCl3) δ ppm 4.00 (s, 3H), 6.80 (d, J = 8.1 Hz, 1H), 7.661.76 (m, 2H), 7.76-7, 91 (m, 2H), 8.28 (d, J = 8.1 Hz, 1H); APCI MS m / z 299 [C13H9F3N2O3 + H]⁺.

Reference example 57

4-Oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbohydrazide [0563] ο ο

<img file="PL2393360T3_D0068.tif" />

[0564] Solution of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (1.019 g, 3.42 mmol) and hydrazine monohydrate (0.3 mL, 6.19 mmol) in ethanol (10 ml) was heated under microwave conditions for 10 minutes at 120 ° C. After this time, the reaction mixture was cooled to room temperature and the product was collected by filtration and washed with cold ethanol to give 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbohydrazide (0.607 g, 60%) as bright orange crystals.

[0565] ¹H NMR (300 MHz, CDCl3) δ ppm 4.34 (d, J = 4.6 Hz, 2H), 6.93 (d, J = 7.8 Hz, 1H), 7.66-7.79 ( m, 2H), 7.86-8.00 (m, 2H), 8.36 (d, J = 7.8 Hz, 1H), 10.98 (br s, 1H); APCI MS m / z 299 [C12H9F3N4O2 + H]⁺.

Reference example 58

4-Oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0566]

<img file="PL2393360T3_D0069.tif" />

[0567] A solution of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (1.007 g, 3.38 mmol) in ammonia (7 N in MeOH, 12 mL, 84 mmol) heated under microwave heating at 100 ° C for 5 minutes. After this time, the reaction mixture was cooled to room temperature and

137 concentrated to give a yellow solid. They were recrystallized from EtOAc to obtain 0.613 g (64%) of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide as colorless crystals.

[0568] ¹H NMR (300 MHz, CDCl3) δ ppm 6.46 (br s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 7.597.80 (m, 2H), 7.84-8 , 01 (m, 2H), 8.38 (d, J = 7.8 Hz, 1H), 9.68 (br s, 1H); APCI MS m / z 284 [M + H]⁺.

Reference example 59

N - [(Dimethylamino) methylidene] -4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0569]

<img file="PL2393360T3_D0070.tif" />

[0570] A suspension of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide (0.54 g, 1.91 mmol) in N, N-dimethylformamide dimethyl acetal (10 mL) was heated under microwave heating at 130 ° C for 15 minutes. After this time, the reaction mixture was cooled in an ice-water bath and the resulting crystals were collected by filtration and washed with hexanes to obtain 0.491 g (76%) N - [(dimethylamino) methylidene] -4-oxo-1- [3 ( trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide as off-white crystals.

¹H NMR (300 MHz, CDCl3) δ ppm 3.16 (s, 3H), 3.22 (s, 3H), 6.72 (d, J = 8.1 Hz, 1H), 7.57-7, 71 (m, 2H), 7.74-7.85 (m, 1H), 7.89 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.70 (s , 1H).

Reference example 60

4-Oxo-N-phenyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0571]

<img file="PL2393360T3_D0071.tif" />

138 [0572] A solution of aniline (0.360 mL, 3.95 mmol) in methylene chloride (10 mL) was cooled in an ice water bath and then treated with a solution of trimethylaluminum (2 M in toluene, 2.0 mL, 4.0 mmol) . After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. At this point, methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (0.595 g, 2.00 mmol) was added and the reaction mixture was heated at reflux for 18 hours. After this time, the reaction mixture was cooled to room temperature and carefully quenched with aqueous HCl (1 N, 5 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3 χ 10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate / hexanes to obtain 0.214 g (30%) 4-oxo-N-phenyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide as yellow crystals.

[0573] ¹H NMR (300 MHz, CDCl3) δ ppm 6.96 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.61-7.85 (m, 4H), 7.88-8.01 (m, 2H), 8.42 (d, J = 7.8 Hz, 1H), 12.19 (br s, 1H); APCI MS m / z 360 [M + H]⁺; temp.top. 181-182 ° C.

Reference example 61

3- [1H-Benzotriazol-1-yl (phenylimino) methyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0574]

<img file="PL2393360T3_D0072.tif" />

[0575] A solution of 4-oxo-N-phenyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide (0.153 g, 0.426 mmol), 1H-benzo [d] [1,2,3 ] triazole (0.201 g, 1.69 mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in methylene chloride (2 mL) was heated under microwave heating at 80 watts for 10 minutes. After this time, the reaction mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes to ethyl acetate) to obtain 0.114 g (58%) 3- [1H-benzotriazol-1-yl (phenylimino) methyl] -1 - [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) one as a bright red solid that was used without additional characterization.

139

Reference example 62

3 - [(4-Piperidin-1-ylphenyl) hydrazone] pentane-2,4-dione [0576] ο ο

<img file="PL2393360T3_D0073.tif" />

[0577] 4-Piperidin-1-ylaniline (510 mg, 2.90 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature, it was cooled to -6 ° C and solid sodium nitrate (200 mg, 2.90 mmol) was added over 10 minutes. Small pieces of ice (50 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2.4-pentanedione (290 mg, 2.90 mmol) and potassium acetate (20 g) in ethanol (250 mL). The solution was stirred for 15 minutes, added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3 - [(4-piperidin-1-ylphenyl) hydrazone] pentane -2,4-dione (570 mg, 68% yield).

[0578] LCMS: m / z = 288 [M⁺+ H].

Reference example 63

3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-piperidin-1-ylphenyl) pyridazin-4 (1H) -one [0579]

<img file="PL2393360T3_D0074.tif" />

[0580] 3 - [(4-Piperidin-1-ylphenyl) hydrazone] pentane-2,4-dione (570 mg, 1.99 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-piperidin-1-ylphenyl) pyridazine-4 (1H ) -one which was used in the next step without further purification.

Reference example 64

3 - [(4-cyclohexylphenyl) hydrazono] pentane-2,4-dione

140 [0581]

<img file="PL2393360T3_D0075.tif" />

[0582] To a solution of 4-cyclohexylaniline (500 mg, 2.86 mmol) in 10 ml acetic acid and 2 ml concentrated hydrochloride solution, sodium nitrate (III) nitrate (237 mg, 3.43 mmol) was added dropwise at 0 ° C in 4 ml of water and the mixture was stirred at 0 ° C for 1 hour. A solution of sodium acetate (703 mg, 8.58 mmol) and acetylacetone (372 mg, 3.72 mmol) in 10 ml ethanol and 6 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(4-cyclohexylphenyl) hydrazone] pentane-2,4-dione (420 mg, 51%).

[0583] ¹H NMR (400 MHz, CDCl3): δ ppm 1.24-1.27 (m, 2H), 1.38-1.43 (m, 4H), 1.851.87 (m, 4H), 2.49- 2.52 (m, 4H), 2.60 (s, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 14.81 (s, 1H).

Reference example 65

1- (4-Cyclohexylphenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one [0584]

<img file="PL2393360T3_D0076.tif" />

[0585] 3 - [(4-Cyclohexylphenyl) hydrazone] pentane-2,4-dione (406 mg, 1.42 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a cooler reflux for 4 hours, then concentrated under reduced pressure to obtain crude 1- (4-cyclohexylphenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without additional purification.

[0586] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 1.25-1.28 (m, 2H), 1.391.44 (m, 4H), 1.86-1.88 (m, 4H), 2, 52-2.54 (m, 1H), 2.90 (s, 3H), 3.13 (s, 3H), 5.62-5.64 (m, 1H), 6.71 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8, 0 Hz, 1H).

141

Reference example 66

4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzonitrile [0587]

<img file="PL2393360T3_D0077.tif" />

CN [0588] 4-Aminobenzonitrile (500 mg, 4.24 mmol) was added to the solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6 ° C. When the mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrate (292 mg, 4.24 mmol) was added over 10 minutes. Small pieces of ice (50 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2.4pentanedione (424 mg, 4.24 mmol) and potassium acetate (20 g) in ethanol (250 mL). The solution was stirred for 15 minutes, added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 4- [2- (1-acetyl-2-oxopropylidene) hydrazine ] benzonitrile (280 mg, 29%).

[0589] ¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.63 (s, 3H), 7.47 (dd, J = 7.2,

1.6 Hz, 2H), 7.70 (dd, J = 7.2, 1.6 Hz, 2H), 14.51 (s, 1H).

Reference example 67

4- {3- [3- (Dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzonitrile [0590]

OO

<img file="PL2393360T3_D0078.tif" />

<img file="PL2393360T3_D0079.tif" />

CN [0591] 4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzonitrile (266 mg, 1.16 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under reflux at reflux for 4 hours, then concentrated under reduced pressure to obtain crude 4- {3- [3- (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzonitrile, which was used in next step without additional purification.

142 [0592] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 2.96 (s, 3H), 3.20 (s, 3H), 6.13 (d, J = 12.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 12.0 Hz, 1H).

Reference example 68

3 - {[4- (Methylsulfonylphenyl] hydrazone} pentane-2,4-dione [0593] ο ο μΛΖ Me ™^ΝΦ

SO₂Me [0594] 4- (Methylsulfonyl) aniline (500 mg, 2.92 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrate (201 mg, 2.92 mmol) was added over 10 minutes. Small pieces of ice (50 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2.4-pentanedione (292 mg, 2.92 mmol) and potassium acetate (20 g) in ethanol (250 mL). The solution was stirred for 15 minutes, added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3 - {[4- (methylsulfonyl) phenyl] hydrazone} pentane -2,4-dione (780 mg, 95%).

[0595] ¹H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 3H), 2.63 (s, 3H), 3.08 (s, 3H), 7.54 (dd, J = 7.2, 2.0 Hz, 2H), 7.98 (dd, J = 7.2, 2.0 Hz, 2H), 14.78 (s, 1H).

Reference example 69

3- [3- (Dimethylamino) prop-2-enoyl] -1- [4- (methylsulfonyl) phenyl] pyridazin-4 (1H) on [0596]

<img file="PL2393360T3_D0080.tif" />

CM ^ Me [0597] 3 - {[4- (Methylsulfonyl) phenyl] hydrazone} pentane-2,4-dione (500 mg, 1.77 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF-DMA ) and the mixture was heated to reflux for 4 hours,

143 then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- [4- (methylsulfonyl) phenyl] pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 70

3 - {[4- (Morpholin-4-ylsulfonyl) phenyl] hydrazone} pentane-2,4-dione [0598]

VI VI, ΛΛ [0599] 4- (Morpholin-4-ylsulfonyl) aniline (300 mg, 1.24 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 room temperature it was cooled to -6 ° C and solid sodium nitrate (85 mg, 1.24 mmol) was added over 10 minutes. Small pieces of ice (50 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2,4-pentanedione (124 mg, 1.24 mmol) and potassium acetate (20 g) in ethanol (250 ml). The solution was stirred for 15 minutes, added to 250 ml of saturated Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3 - {[4- (morpholin-4-ylsulfonyl) phenyl] hydrazono} pentane-2,4-dione (375 mg, 86%).

[0600] ¹H NMR (400 MHz, CDCl3): δ ppm 2.53 (s, 3H), 2.64 (s, 3H), 3.03 (t, J = 4.8 Hz, 4H), 3.76 (t , J = 4.8 Hz, 4H), 7.54 (dd, J = 7.2, 2.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 14.56 (s, 1H).

Reference example 71

3- [3- (Dimethylamino) prop-2-enoyl] -1- [4- (morpholin-4-ylsulfonyl) phenyl] pyridazin 4 (1H) -one [0601]

<img file="PL2393360T3_D0081.tif" />

[0602] 3 - {[4- (Morpholin-4-ylsulfonyl) phenyl] hydrazone} pentane-2,4-dione (300 mg, 0.85 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal (DMF144

DMA) and the mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain crude 3- [3- (dimethylamino) prop-2-enoyl] -1- [4- (morpholin-4-ylsulfonyl) phenyl ] pyridazine-4 (1H) one which was used in the next step without further purification.

Reference example 72

4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzamide [0603]

<img file="PL2393360T3_D0082.tif" />

[0604] 4-Aminobenzamide (1000 mg, 7.36 mmol) was added to a solution of 6 mL phosphoric acid (85%) and 4 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrate (508 mg, 7.36 mmol) was added over 10 minutes. Small pieces of ice (100 g) were added to the solution. The mixture was added at 0 ° C to a suspension of the corresponding 2.4-pentanedione (736 mg, 7.36 mmol) and potassium acetate (40 g) in ethanol (400 mL). The solution was stirred for 15 minutes, added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 4- [2- (1-acetyl-2-oxopropylidene) hydrazine ] benzamide (460 mg, 25%).

[0605] ¹H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 3H), 2.62 (s, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.88 (d , J = 8.4 Hz, 2H), 14.62 (s, 1H).

Reference example 73

4- {3- [3- (Dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzamide [0606]

<img file="PL2393360T3_D0083.tif" />

CONH₂ [0607] 4- [2- (1-Acetyl-2-oxopropylidene) hydrazine] benzamide (540 mg, 2.19 mmol) was dissolved in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and the mixture was heated under a condenser reflux for 4 hours,

145 then concentrated under reduced pressure to obtain crude 4- {3- [3- (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzamide, which was used in the next step without further purification.

[0608] ¹H NMR crude product (400 MHz, CDCl3): δ ppm 2.91 (s, 3H), 3.14 (s, 3H), 5.60-5.62 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 9.2 Hz, 2H), 8.67 (s, 1H).

Reference example 74

Methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazone} pentanoate [0609]

<img file="PL2393360T3_D0084.tif" />

[0610] A suspension of 3- (trifluoromethyl) aniline (8.03 g, 50 mmol) in 6 N HCl (50 mL) was cooled to 0 ° C and treated dropwise with a solution of sodium nitrate (III) (4.10 g, 60 mmol) in water (10 ml). The resulting pale yellow solution was poured into a suspension of methyl propionyl acetate (6.50 g, 50 mmol) and sodium acetate (24.00 g, 292 mmol) in ethanol (80 ml), pre-cooled to 0 ° C. The resulting yellow / orange suspension was stirred for 30 minutes. The product was collected by filtration and washed with water (100 ml). The crude material was dissolved in ethyl acetate (100 mL) and dried (Na2SO4). The product recrystallized during concentration of ethyl acetate to obtain (14.00 g, 93%) of methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazono} pentanoate as a yellow / orange solid.

[0611] ¹1 H NMR (500 MHz, CDCl 3) shows a mixture of isomers. Main isomer δ ppm 1.18 (t, J = 7.5 Hz, 3H), 2.96 (q, J = 7.5 Hz, 2H), 3.92 (s, 3H), 7.39-7 , 42 (m, 1H), 7.48-7.55 (m, 2H), 7.56 (s, 1H), 12.75 (br s, 1H); Secondary isomer δ ppm 1.15 (t, J = 7.5 Hz, 3H), 3.04 (q, J = 7.5, 2H), 3.90 (s, 3H), 7.39-7, 42 (m, 1H), 7.48-7.55 (m, 2H), 7.67 (s, 1H), 14.76 (br s, 1H); ESI MS m / z 303 [M + H]⁺.

Reference example 75

Methyl 5-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate [0612]

146

<img file="PL2393360T3_D0085.tif" />

[0613] A solution of methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazone} pentanoate (4.00 g, 13.2 mmol) in N, N-dimethylformamide dimethyl acetal (33 ml) was heated at reflux temperature for 2.5 hours. After this time, the reaction mixture was cooled to room temperature and the resulting solid was collected by filtration and washed with a small amount of hexanes to give 5-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine Methyl-3-carboxylate (3.55 g, 87%) as a pale yellow solid.

[0614] ¹H NMR (500 MHz, CDCl3) δ 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- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0615]

<img file="PL2393360T3_D0086.tif" />

[0616] To a stirred suspension of N, O-dimethylhydroxylamine hydrochloride (0.468 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise trimethylaluminum (2.4 mL, 4.8 mmol, 2 M solution in toluene) at 0 ° C. After the addition, the suspension was stirred at 0 ° C for 10 minutes and then at room temperature for 30 minutes to obtain a homogeneous solution. The flask was then re-cooled in an ice bath. In a separate flask, methyl 5-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (0.500 g, 1.6 mmol) in dichloromethane (5 mL) was dissolved and added dropwise and allowed to stir for 2 hours. The reaction was quenched with water (5 mL) and 2 N aqueous HCl (2 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to give N-methoxy-N, 5-dimethyl-4-oxo-1- [3147 (trifluoromethyl) phenyl] -1,4- dihydropyridazine-3-carboxamide (0.535 g, 98%) as a yellow solid.

[0617] ¹H NMR (500 MHz, CDCl3) δ ppm 2.18 (s, 3H), 3.41 (s, 3H), 3.68 (s, 3H), 7.663.70 (m, 2H), 7.80- 7.90 (m, 2H), 8.21 (s, 1H); APCI MS m / z 342 [M + H]⁺.

Reference example 77

3-Acetyl-5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0618]

<img file="PL2393360T3_D0087.tif" />

[0619] For a solution of N-methoxy-N, 5-dimethyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide (0.535 g, 1.6 mmol) in THF (10 ml) at -78 ° C methylmagnesium bromide (1.1 ml, 3.2 mmol, 3 M in diethyl ether) was added. The reaction mixture was stirred at this temperature for 1 hour and then quenched with saturated aqueous ammonium chloride solution (5 mL) and 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 (2 x 10 mL) and the combined organic extracts were washed with 1 N aqueous HCl (15 mL), brine (15 mL), dried (Na 2 SO 4), filtered and concentrated to give 3-acetyl 5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) one (0.463 g, 98%) as a pale yellow solid.

[0620] ¹H NMR (500 MHz, CDCl3) δ 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

3- [3- (Dimethylamino) prop-2-enoyl] -5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0621]

<img file="PL2393360T3_D0088.tif" />

148 [0622] Microwave vial containing 3-acetyl-5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.363 g, 1.2 mmol) and N, N-dimethylformamide dimethyl acetal (2, 5 ml) was heated at 120 ° C for 20 minutes. The crude material was concentrated and purified by flash column chromatography (silica gel; methylene chloride to 1: 9 methanol / methylene chloride) to give 3- [3- (dimethylamino) prop-2-enoyl] -5-methyl-1- [ 3- (trifluoromethyl) phenyl] pyridazin-4 (1H) one (0.365 g, 87%) as an orange solid.

[0623] ¹H NMR (300 MHz, CDCl3) δ ppm 2.18 (s, 3H), 2.92 (s, 3H), 3.14 (s, 3H), 5.695,82 (m, 1H), 7.63- 7.65 (m, 2H), 7.83-7.87 (m, 3H), 8.20 (s, 1H); APCI MS m / z 352 [M + H]⁺.

Reference example 79

3- [3- (Dimethylamino) but-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0624]

OO Me

<img file="PL2393360T3_D0089.tif" />

[0625] A suspension of 3-acetyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.369 g, 1.30 mmol) in N, N-dimethylacetamide dimethyl acetal (3.5 mL, 18 , 3 mmol) was heated under microwave conditions at 120 ° C for 5 minutes. After this time, the reaction mixture was cooled to room temperature and concentrated on silica gel. The crude product was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol) to give 3 [3- (dimethylamino) but-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 ( 1H) -one (0.314 g, 68%) as a yellow foam.

[0626] ¹H NMR (500 MHz, CDCl3) δ ppm 2.71 (s, 3H), 3.07 (br s, 6H), 5.52 (s, 1H), 6.71 (d, J = 8.0 Hz , 1H), 7.59-7.69 (m, 2H), 7.76-7.85 (m, 1H), 7.87 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H); APCI MS m / z 352 [M + H]⁺.

Reference example 80

Methyl 2 - [(2-Fluoro-phenyl)-hydrazono] -4-methoxy-3-oxo-butanoate [0627]

149

Μο ° Υγ%_Μβ· ην^ν

Υ) [0628] A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0 ° C to a mixture of 2-fluoroaniline (1.93 mL, 20 mmol) and 6 M aqueous HCl ( 20 ml, 120 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled to 0 ° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give the title compound (5.03 g, 94% yield) as pale yellow crystals: m.p. 121-126 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.94 (3H, s), 4.68 (2H, s), 7.08-7.25 (3H, m) , 7.63 (1H, dt, J = 1.5, 7.9 Hz), 13.06 (1H, br s). Anal. calc. for C12H13FN2O4: C, 53.73; H, 4.88; N, 10.44. Found: C, 53.69; H, 4.96; N, 10.47.

Reference example 81

Methyl 1- (2-Fluoro-phenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0629]

<img file="PL2393360T3_D0090.tif" />

[0630] A solution of methyl 2 - [(2-fluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate (5.02 g, 18.7 mmol) in N, N-dimethylformamide dimethyl acetal (35 ml) was heated to reflux. at reflux for 1 hour. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane / AcOEt (2/1) to give the title compound (4.70 g, 90% yield) as off-white crystals: m.p. 155-157 ° C;¹H NMR (300 MHz, CDCl3): δ 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, J = 2.3 Hz). Anal. calc. for C13H11FN2O4: C, 56.12; H, 3.98; N, 10.07. Found: C, 56.17; H, 3.97; N, 10.25.

150

Reference example 82

1- (2-Fluoro-phenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0631] ο ο

ΜβθΑξΛ_Ν Me li Ν OM®

<img file="PL2393360T3_D0091.tif" />

[0632] To a solution of N, O-dimethylhydroxylamine hydrochloride (4.74 g, 48.6 mmol) and iPr2NEt (8.47 mL, 48.6 mmol) in CH2Cl2 (50 mL) was added dropwise AlMe3 (1.8 M solution) in toluene, 27 ml, 48.6 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 1- (2-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.51 g, 16.2 mmol) in CH2Cl2 (50 ml) was added dropwise. and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice-water, acidified with 1 M aqueous HCl, saturated with NaCl and extracted with AcOEt five times. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (3.23 g, 65% yield) as colorless crystals: m.p. 152-154 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.71 (3H, s), 3.91 (3H, s), 7.25-7.33 (2H, m) , 7.41-7.48 (1H, m), 7.65 (1H, dt, J = 1.9, 7.9 Hz), 7.81 (1H, d, J = 2.3 Hz). Anal. calc. for C14H14FN3O4: C, 54.72; H, 4.59; N, 13.67. Found: C, 54.85; H, 4.54; N, 13.86.

Reference example 83

3-Acetyl-1- (2-fluorophenyl) -5-methoxypyridazin-4 (1H) -one [0633]

<img file="PL2393360T3_D0092.tif" />

[0634] MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at -78 ° C to a solution of 1- (2-fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1 , 4-dihydropyridazine-3-carboxamide (3.20 g, 10.4 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was quenched with 1 M aqueous HCl, saturated with NaCl and extracted with AcOEt five times. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (2.32 g, 85% yield)

151 as pale yellow crystals: m.p. 154-156 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.91 (3H, s), 7.27-7.38 (2H, m), 7.45-7.53 ( 1H, m), 7.65 (1H, dt, J = 1.5, 7.9 Hz), 7.77 (1H, d, J = 2.3 Hz). Anal. calc. for C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.62; H, 4.22; N, 10.79.

Reference example 84

Methyl 2 - {[2- (Difluoromethoxy) phenyl] hydrazono} -4-methoxy-3-oxobutanoate [0635] ο ο ην^μ [0636] A solution of NaNO2 (2.378 g, 34.5 mmol) in H2O (10 mL) was added dropwise at 0 ° C to a solution of 2- (difluoromethoxy) aniline (3.59 mL, 28.7 mmol) in 6M aqueous HCl solution (28.7 mL, 172 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.72 mL, 28.7 mmol) and NaOAc (14.14 g, 172 mmol) in MeOH (50 mL) pre-cooled to 0 ° C. The precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was washed with water, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was washed with hexane / AcOEt (3/1) to give the title compound (8.70 g, 96% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.89 (3H χ 0.5, s), 3.94 (3H χ 0.5, s), 4.68 ( 1H χ 0.5, s), 4.70 (1H χ 0.5, s), 6.63 (1H χ 0.5, t, J = 72.7 Hz), 6.66 (1H χ 0, 5, t, J = 72.3 Hz), 7.10-7.34 (4H, m), 7.67 (1H χ 0.5, dd, J = 8.3, 1.5 Hz), 7 , 90 (1H χ 0.5, dd, J = 8.3, 1.5 Hz), 13.14 (1H χ 0.5, s),

14.96 (1H χ 0.5, brs).

Reference example 85

Methyl 1- [2- (Difluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0637]

<img file="PL2393360T3_D0093.tif" />

152 [0638] A solution of methyl 2 - {[2- (difluoromethoxy) phenyl] hydrazone} -4-methoxy-3-oxobutanoate (8.70 g, 27.5 mmol) in N, N-dimethylformamide dimethyl acetal (60 mL) was heated under reflux at reflux for 3 hours and stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with hexane / AcOEt (3/1) to give the title compound (7.92 g, 88% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 3.96 (3H, s), 6.55 (1H, d, J = 72.7 Hz), 7.35-7 , 45 (2H, m), 7.49-7.56 (1H, m), 7.61 (1H, dd, J = 7.9, 1.5 Hz), 7.73 (1H, s).

Reference example 86

1- [2- (Difluoromethoxy) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0639]

Me [0640] To a solution of N, O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added dropwise with AlMe3 (1.8 M toluene solution, 30.0 mL, 54.0 mmol) at 0 ° C. After stirring at 0 ° C for 1 hour, a solution of methyl 1- [2- (difluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5.87 g, 17.99) was added dropwise. mmol) in CH 2 Cl 2 (60 mL) and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with hexane / AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 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, s).

Reference example 87

3-Acetyl-1- [2- (difluoromethoxy) phenyl] -5-methoxypyridazin-4 (1H) -one [0641]

Μθ

153 [0642] MeMgBr (1 M solution in THF, 40.4 mL, 40.4 mmol) was added dropwise at -78 ° C to a solution of 1- [2- (difluoromethoxy) phenyl] -N, 5-dimethoxy-N- methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.79 g, 13.48 mmol) in THF (500 mL). After stirring for 1 hour, the reaction mixture was quenched with 1 M aqueous HCl solution and warmed to room temperature. The reaction mixture was concentrated under reduced pressure and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1 / 1-0 / 1) and recrystallized from diisopropyl ether / AcOEt to give the title compound (3.33 g, 80% yield) as colorless crystals:¹H NMR (300 MHz, CDCl3): δ ppm 2.68 (3H, s), 3.89 (3H, s), 6.55 (1H, t, J = 72.7 Hz), 7.36-7 , 45 (2H, m), 7.50 - 7.57 (1H, m), 7.61 (1H, dd, J = 7.8, 1.7 Hz), 7.72 (1H, s).

Reference example 88

1- [2- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazin-4 (1H) -one [0643]

<img file="PL2393360T3_D0094.tif" />

[0644] A mixture of 3-acetyl-1- [2- (difluoromethoxy) phenyl] -5-methoxypyridazin-4 (1H) one (3.70 g, 11.93 mmol) and N, N-dimethylformamide dimethyl acetal (50 ml ) was refluxed for 5 hours and stirred overnight at room temperature. The precipitate was collected by filtration and washed with AcOEt to give the title compound (4.07 g, 93% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 2.90 (3H, s), 3.12 (3H, br s), 3.87 (3H, s), 5.87 (1H, br s), 6 , 31-6.82 (2H, m), 7.30-7.41 (2H, m), 7.43-7.50 (1H, m), 7.63 (1H, dd, J = 7, 8, 1.8 Hz), 7.74 (1H, s).

Reference example 89

Methyl 4-methoxy-3-oxo-2- {[3- (trifluoromethyl) phenyl] hydrazone} butanoate [0645]

154

<img file="PL2393360T3_D0095.tif" />

[0646] A solution of NaNO2 (4.14 g, 60 mmol) in H2O (15 mL) was added dropwise at 0 ° C to a mixture of 3- (trifluoromethyl) aniline (6.24 mL, 50 mmol) and 6 M aqueous HCl solution (50 ml, 300 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (7.31 mL, 50 mmol) and NaOAc (24.6 g, 300 mmol) in EtOH (80 mL) pre-cooled at 0 ° C. The precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was crystallized from hexane / AcOEt to give the title compound (14.0 g, 88% yield) as pale yellow crystals:

¹H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H χ 0.36, s), 3.52 (3H χ 0.64, s), 3.90 (3H χ 0.36, s), 3.94 (3H χ 0.64, s), 4.68 (2H χ 0.64, s), 4.70 (2H χ 0.36, s), 7.41-7.59 (3H + 1H χ 0.64, m), 7.71 (1H χ 0.36, s), 13.00 (1H χ 0.64, s), 14.87 (1H χ 0.36, s).

Reference example 90

Methyl 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate [0647] oo

<img file="PL2393360T3_D0096.tif" />

[0648] A solution of methyl 4-methoxy-3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazone} butanoate (14.0 g, 44 mmol) in N, N-dimethylformamide dimethyl acetal (100 mL) was heated under reflux condenser at reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane / AcOEt (3/1) to give the title compound (12.9 g, 89% yield) as off-white crystals: m.p. 169-170 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 3.99 (3H, s), 7.66-7.74 (2H, m), 7.83-7.89 ( 2H, m), 7.95 (1H, s). Anal. calc. for C14H11F3N2O4: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.15; H, 3.47 N,

8,60.

155

Reference example 91

N, 5-Dimethoxy-N-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0649]

IL ^ .N ÓMe

<img file="PL2393360T3_D0097.tif" />

[0650] To a solution of N, O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added dropwise AlMe3 (1.8 M solution in toluene, 15 ml, 27 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (2.95 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise. ) and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane / AcOEt to give the title compound (2.15 g, 67% yield) as off-white crystals: m.p. 170-171 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.63-7.71 (2H, m) , 7.80-7.86 (1H, m), 7.88 (1H, s), 7.98 (1H, s). Anal. calc. for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.48; H, 4.07; N, 11.66.

Reference example 92

3-Acetyl-5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0651]

<img file="PL2393360T3_D0098.tif" />

[0652] MeMgBr (3 M solution in diethyl ether, 4 mL, 12 mmol) was added dropwise at -78 ° C to a solution of N, 5-dimethoxy-N-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl ] -1,4-dihydropyridazine-3-carboxamide (2.09 g, 5.85 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with AcOEt three times. The combined extracts were washed with brine, dried over MgSO 4 and concentrated under

156 reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt / MeOH (1 / 0-10 / 1) and recrystallized from hexane / AcOEt to give the title compound (1.44 g, 79% yield) as off-white crystals: temp .top. 155-156 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.71 (3H, s), 3.98 (3H, s), 7.68-7.76 (2H, m), 7.83-7.88 ( 2H, m), 7.94 (1H, s). Anal. calc. for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.79; H, 3.59; N, 9.02.

Reference example 93

3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0653]

<img file="PL2393360T3_D0099.tif" />

[0654] A solution of 3-acetyl-5-methoxy-1- [3- (tritluoromethyl) phenyl] pyridazin-4 (1H) -one (1.39 g, 4.45 mmol) in N, N-dimethylformamide dimethyl acetal ( 15 ml) was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in AcOEt. The organic solution was washed with half saturated brine and the aqueous solution was extracted with AcOEt four times. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (1.46 g, 89% yield) as orange crystals: m.p. 176-178 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, J = 13, 2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, br s), 7.84-7.90 (2H, m), 7.96 (1H, s). Anal. calc. for C17H16F3N3O3: C, 55.59; H, 4.39; N, 11.44. Found: C, 55.32; H, 4.51; N, 11.30.

Reference example 94

Methyl 2 - [(2-Fluoro-4-iodophenyl) hydrazono] -4-methoxy-3-oxobutanoate [0655]

157

<img file="PL2393360T3_D0100.tif" />

[0656] A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0 ° C to a mixture of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) and 6 M aqueous solution HCl (20 mL, 120 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled at 0 ° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give the title compound (6.29 g, 80% yield) as yellow crystals: m.p. 141-146 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.50 (3H, s), 3.93 (3H, s), 4.64 (2H, s), 7.35 (1H, t, J = 8, 5 Hz), 7.49-7.55 (2H, m), 12.97 (1H, br s). Anal. calc. for C12H12FIN2O4: C, 36.57; H, 3.07; N, 7.11. Found: C, 36.74; H, 3.10; N, 7.32.,

Reference example 95

Methyl 1- (2-Fluoro-4-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0657]

<img file="PL2393360T3_D0101.tif" />

[0658] A solution of methyl 2 - [(2-fluoro-4-iodophenyl) hydrazone] -4-methoxy-3-oxobutanoate (6.27 g, 15.9 mmol) in N, N-dimethylformamide dimethyl acetal (60 ml) refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (3.77 g, 59% yield) as off-white crystals: m.p. 160-162 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 3.97 (3H, s), 7.36-7.41 (1H, m), 7.64-7.70 ( 2H, m), 7.73 (1H, d, J = 2.6 Hz). Anal. calc. for C13H10FIN2O4: C, 38.64; H, 2.49; N, 6.93. Found: C, 38.68; H, 2.59; N, 6.98.

158

Reference example 96

1- (2-Fluoro-4-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0659]

<img file="PL2393360T3_D0102.tif" />

[0660] To a solution of N, O-dimethylhydroxylamine hydrochloride (8.78 g, 90 mmol) and iPr2NEt (15.7 mL, 90 mmol) in CH2Cl2 (100 mL) was slowly added AlMe3 (1.8 M solution in toluene, 50 ml, 90 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 1- (2-fluoro-4-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (12.1 g, 30 mmol) in CH2Cl2 (100) ml) and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice water and the organic layer was separated. The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (9.96 g, 77% yield) as a white amorphous solid:¹H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.70 (3H, s), 3.90 (3H, s), 7.39 (1H, t, J = 8, 1 Hz), 7.63-7.67 (2H, m), 7.77 (1H, d, J = 2.3 Hz).

Reference example 97

3-Acetyl-1- (2-fluoro-4-iodophenyl) -5-methoxypyridazin-4 (1H) -one [0661]

<img file="PL2393360T3_D0103.tif" />

I [0662] MeMgBr (1 M solution in THF, 70 mL, 70 mmol) was added dropwise at -78 ° C to a solution of 1- (2-fluoro-4-iodophenyl) -N, 5-dimethoxy-N-methyl- 4-oxo-1,4-dihydropyridazine-3-carboxamide (9.96 g, 23 mmol) in THF (250 mL). After stirring for 1 hour, the reaction mixture was quenched with 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt i

159 recrystallized from MeOH to give the title compound (2.05 g, 23% yield) as pale yellow crystals: m.p. 196-198 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.90 (3H, s), 7.36-7.41 (1H, m), 7.66-7.71 ( 2H, m), 7.73 (1H, d, J = 2.6 Hz). Anal. calc. for C13H10FIN2O3: C, 40.23; H, 2.60; N, 7.22. Found: C, 40.25; H, 2.87; N, 7.28.

Reference example 98

Methyl 5- (methoxymethyl) -4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate [0663]

<img file="PL2393360T3_D0104.tif" />

[0664] A solution of NaNO2 (2.48 g, 36 mmol) in H2O (10 mL) was added dropwise at 0 ° C to a mixture of 3- (trifluoromethyl) aniline (3.75 mL, 30 mmol) and 6 M aqueous HCl solution (30 ml, 180 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 5-methoxy-3-oxo-valerate (4.37 mL, 30 mmol) and NaOAc (14.8 g, 180 mmol) in EtOH (50 mL) pre-cooled at 0 ° C. After stirring for 5 minutes, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure.

[0665] A solution of the residue in N, N-dimethylformamide dimethyl acetal (50 mL) was refluxed at reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from AcOEt to give the title compound (7.13 g, 69% yield) as a yellow solid: m.p. 138-140 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.53 (3H, s), 4.00 (3H, s), 4.49 (2H, d, J = 1.5 Hz), 7.65-7 , 73 (2H, m), 7.82-7.85 (1H, m), 7.89 (1H, s), 8.38 (1H, t, J = 1.5 Hz). Anal. calc. for C15H13F3N2O4: C, 52.64; H, 3.83; N, 8.18. Found: C, 52.50; H, 3.89; N, 8.17.

Reference example 99

N-Methoxy-5- (methoxymethyl) -N-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide [0666]

160

<img file="PL2393360T3_D0105.tif" />

[0667] To a solution of N, O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added dropwise AlMe3 (1.8 M solution in toluene, 15 ml, 27 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 5- (methoxymethyl) -4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (3.08 g, 9 mmol) in CH2Cl2 was added dropwise. (30 ml) and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane / AcOEt to give the title compound (1.99 g, 60% yield) as an off-white solid: m.p. 157-159 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.53 (3H, s), 3.67 (3H, s), 4.50 (2H, d, J = 1, 1 Hz), 7.62-7.71 (2H, m), 7.79-7.85 (1H, m), 7.90 (1H, s), 8.39 (1H, t, J = 1 , 1 Hz). Anal. calc. for C16H16F3N3O4: C, 51.75; H, 4.34; N, 11.32. Found: C, 51.77; H, 4.25; N, 11.24.

Reference example 100

3-Acetyl-5- (methoxymethyl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0668]

<img file="PL2393360T3_D0106.tif" />

[0669] MeMgBr (1 M solution in THF, 16 mL, 16 mmol) was added dropwise at -78 ° C to a solution of N-methoxy-5- (methoxymethyl) -N-methyl-4-oxo-1- [3 ( trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide (1.95 g, 5.25 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane / AcOEt to give the title compound (1.42 g, 83% yield) as a pale yellow solid:

161 temp.top. 141-143 ° C;¹H NMR (300 MHz, CDCl3): δ 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. calc. for C15H13F3N2O3: C, 55.22; H, 4.02; N, 8.59. Found: C, 55.26; H, 3.95; N, 8.58.

Reference example 101

3-Acetyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0670]

<img file="PL2393360T3_D0107.tif" />

[0671] A mixture of 3 - {[3- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione (5.00 g, 18.4 mmol) and N, N-dimethylformamide dimethyl acetal (2.44 mL, 18 , 4 mmol) in DMF (100 ml) was heated to 80 ° C for 4 hours. The mixture was diluted with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 80/20) and triturated with EtOAc / hexane to give the title compound (3.38 g, 65% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 2.55 (3H, s), 6.75 (1H, d, J = 8.0 Hz), 7.78-7.88 (2H, m) , 8.06-8.16 (2H, m), 8.96 (1H, d, J = 8.2 Hz).

Reference example 102

3-Acetyl-5-bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0672]

<img file="PL2393360T3_D0108.tif" />

[0673] To a solution of 3-acetyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (1.00 g, 3.54 mmol) in AcOH (3.5 mL) was added Br2 (0.181) ml, 3.54 mmol) at temperature

162 room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and aqueous NaHCO3, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to give the title compound (332 mg, 26% yield) as a pale yellow solid:¹H NMR (DMSO-d6, 300 MHz): δ 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) phenyl] -1,6-dihydropyridazine-3-carboxylate [0674] [0675] A solution of NaNO2 (2.07 g, 30 mmol) in H2O (10 mL) were added dropwise at 0 ° C to a mixture of 3- (trifluoromethyl) aniline (3.12 mL, 25 mmol) and 6 M aqueous HCl (25 mL, 150 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of dimethyl 1,3-acetonodicarboxylate (3.61 mL, 25 mmol) and NaOAc (12.3 g, 150 mmol) in EtOH (40 mL) pre-cooled at 0 ° C. After stirring for 10 minutes, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure.

[0676] A solution of the residue and NaOMe (2.70 g, 50 mmol) in MeOH (50 mL) was stirred for 30 minutes at room temperature. The reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure.

[0677] A suspension of residue, Mel (3.11 mL, 50 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF (50 mL) was stirred for 1 hour 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 4 and concentrated 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:

163 temp.top. 124-125 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.94 (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. calc. for C14H11F3N2O4: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.29; H, 3.40; N, 8.52.

Reference example 104

N, 4-Dimethoxy-N-methyl-6-oxo-1- [3- (trifluoromethyl) phenyl] -1,6-dihydropyridazine-3-carboxamide [0678]

<img file="PL2393360T3_D0109.tif" />

[0679] To a solution of N, O-dimethylhydroxylamine hydrochloride (1.58 g, 16.2 mmol) and iPr2NEt (2.82 mL, 16.2 mmol) in CH2Cl2 (13 mL) was added dropwise AlMe3 (1.8 M solution) in toluene, 9.0 mL, 16.2 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 4-methoxy-6-oxo-1- [3- (trifluoromethyl) phenyl] -1,6-dihydropyridazine-3-carboxylate (1.77 g, 5.4 mmol) in CH 2 Cl 2 () was added dropwise. 15 ml) and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane / AcOEt to give the title compound (1.48 g, 83% yield) as a white solid: m.p. 127-129 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.37 (3H, s), 3.64 (3H, s), 3.91 (3H, s), 6.30 (1H, s), 7.55 -7.60 (1H, m), 7.62-7.65 (1H, m), 7.82-7.86 (1H, m), 7.88 (1H, s). Anal. calc. for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.47; H, 3.99; N, 11.83.

Reference example 105

6-Acetyl-5-methoxy-2- [3- (trifluoromethyl) phenyl] pyridazin-3 (2H) -one [0680]

<img file="PL2393360T3_D0110.tif" />

164 [0681] 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-1- [3- (trifluoromethyl) phenyl ] -1,6-dihydropyridazine-3-carboxamide (1.43 g, 4 mmol) in THF (15 mL). After stirring for 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1/1) and recrystallized from hexane / AcOEt to give the title compound (566 mg, 45% yield) as a white solid: m.p. 136-138 ° C;¹H NMR (300 MHz, CDCl3): δ 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. calc. for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.96; H, 3.57; N, 8.96.

Reference example 106

5-Methoxy-6- (1-phenyl-1H-pyrazol-5-yl) -2- [3- (trifluoromethyl) phenyl] pyridazin 3 (2H) -one [0682]

<img file="PL2393360T3_D0111.tif" />

[0683] A solution of 6-acetyl-5-methoxy-2- [3- (trifluoromethyl) phenyl] pyridazin-3 (2H) -one (540 mg, 1.73 mmol) in N, N-dimethylformamide dimethyl acetal (5 mL ) was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure.

[0684] A solution of the residue and phenylhydrazine (0.551 mL, 5.19 mmol) in MeOH (5 mL) was refluxed at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1/1) and recrystallized from hexane / AcOEt to give

165 of the title compound (323 mg, 45% yield) as a white solid: m.p. 165-167 ° C;¹H NMR (300 MHz, CDCl3): δ 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. calc. for C21H15F3N4O2: 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-dihydropyridazine-3-carboxylic acid [0685]

<img file="PL2393360T3_D0112.tif" />

[0686] To a suspension of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (10.0 g, 33.5 mmol) in MeOH (150 mL) was added 1 M aqueous solution NaOH (50 ml) at 0 ° C. The mixture was stirred at room temperature for 30 minutes. A 1 M aqueous HCl solution (50 ml) was added to the suspension at 0 ° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried under vacuum at 50 ° C to obtain the title compound (9.25 g, 97% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ 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 [0687]

<img file="PL2393360T3_D0113.tif" />

166 [0688] A mixture of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylic acid (2.00 g, 7.04 mmol) and CDI (1.26 g, 7.74 mmol ) in THF (20 ml) was heated to 40 ° C for 2 hours. To the solution, N-methoxymethanamine hydrochloride (1.03 g, 10.6 mmol) and i-Pr2NEt (1.84 mL, 10.6 mmol) were added at room temperature. The solution was stirred at room temperature for 20 hours. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 80/20) to obtain the crude title compound (2.40 g) as a pale yellow solid: ¹H NMR (DMSOd6, 300 MHz): δ ppm 3.28 (3H, s), 3.61 (3H, s), 6.67 (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).

Reference example 109

3-Propanoyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0689]

<img file="PL2393360T3_D0114.tif" />

[0690] For a solution of N-methoxy-N-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide (1.20 g, 3.52 mmol) in THF (20 ml) EtMgBr (1.0 M in THF, 7.04 ml, 7.04 mmol) was added at -78 ° C under N2, The mixture was stirred at -78 ° C for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution at -78 ° C. The mixture was warmed to room temperature, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to give the title compound (767 mg, 74% yield) as a light yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ 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 (2H, m), 8.97 (1H, d, J = 8.3 Hz).

167

Reference example 110

4-Bromo-3-phenyl-1H-pyrazole [0691]

CJ [0692] A solution of 3-phenyl-1H-pyrazole (4.08 g, 28.3 mmol) and NBS (5.04 g, 28.3 mmol) in DMF (40 mL) was stirred for 1 hour 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 4 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give the title compound (5.84 g, 93% yield) as a white solid: m.p. 114-116 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 7.39-7.50 (3H, m), 7.64 (1H, s), 7.77 (2H, d, J = 6.8 Hz), 10 , 73 (IH, brs).

Reference example 111

4-Bromo-3-phenyl-1-trityl-1H-pyrazole [0693]

<img file="PL2393360T3_D0115.tif" />

[0694] A suspension of 4-bromo-3-phenyl-1H-pyrazole (6.13 g, 27.5 mmol), trityl chloride (15.3 g, 55.0 mmol) and K2CO3 (11.4 g, 82, 5 mmol) in DMF (100 ml) was stirred for 60 hours at 90 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO 4, concentrated under reduced pressure. The residue was recrystallized from hexane / THF to give the title compound (8.00 g, 63% yield) as a white solid: m.p. 181-183 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), 7.87-7.91 (2H, m). Anal. calc. for C28H21BrN2: C, 72.26; H, 4.55; N, 6.02. Found: C, 72.43; H, 4.66; N, 5.91.

Reference example 112

3-Amino-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0695]

168

<img file="PL2393360T3_D0116.tif" />

[0696] 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 Et3N (3.65 mL, 26.4 mmol) in toluene (35 mL) was heated to 100 ° C for 2 hours. An 8 M aqueous NaOH solution (22 ml) was added to the mixture at 0 ° C. The mixture was stirred at room temperature for 2 hours, diluted with brine, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc / i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and washed with EtOAc / hexane to give the title compound (2.50 g, 56% yield) as pale yellow solid body:¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.17 (1H, d, J = 7.5 Hz), 6.52 (2H, brs), 7.67-7.81 (2H, m) , 8.04 (1H, d, J = 7.5 Hz), 8.10 (1H, s), 8.75 (1H, d, J = 7.5 Hz).

Reference example 113

3-Bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0697]

<img file="PL2393360T3_D0117.tif" />

[0698] To DMF (18 mL) wasoamyl (III) nitrate (2.44 mL, 18.3 mmol) and CuBr2 (1.89 g, 8.46 mmol) were added at 0 ° C. To the mixture, a solution of 3-amino-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (1.80 g, 7.05 mmol) in DMF (7.2 mL) was added dropwise at 0 ° C. . The mixture was stirred at 0 ° C for 1 hour and at 60 ° C for 3 hours. The mixture was diluted with brine, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and triturated powder from

169 hexane to obtain the title compound (1.85 g, 82% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.64 (1H, d, J = 7.7 Hz), 7.78-7.87 (2H, m), 8.01-8.07 ( 1H, m), 8.08 (1H, s), 9.00 (1H, d, J = 7.7 Hz).

Reference example 114

1- [3- (Trifluoromethyl) phenyl] -3 - [(trimethylsilyl) ethynyl] pyridazin-4 (1H) -one [0699]

<img file="PL2393360T3_D0118.tif" />

[0700] A mixture of 3-bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (500 mg, 1.57 mmol), (trimethylsilyl) acetylene (0.222 mL, 1.57 mmol), Et3N (0.329 ml, 2.36 mmol), CuI (4.5 mg, 0.0236 mmol), Pd (PPh3) 2Cl2 (55.1 mg, 0.0785 mmol) and PPh3 (10.3 mg, 0, 0393 mmol) in THF (7.5 ml) was heated to 40 ° C for 8 hours under Ar. To the suspension, (trimethylsilyl) acetylene (0.111 mL, 0.785 mmol) was added. The suspension was heated to 40 ° C for 14 hours under Ar. To the suspension, (trimethylsilyl) acetylene (0.0888 mL, 0.628 mmol) was added. The suspension was heated to 40 ° C for 96 hours under Ar. The mixture was diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to give the title compound (148 mg, yield 28%) as a brown solid:¹H NMR (DMSO-d6, 300 MHz): δ ppm 0.26 (9H, s), 6.64 (1H, d, J = 7.9 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) phenyl] pyridazin-4 (1H) -one [0701]

<img file="PL2393360T3_D0119.tif" />

170 [0702] A mixture of 1- [3- (trifluoromethyl) phenyl] -3 - [(trimethylsilyl) ethynyl] pyridazin 4 (1H) -one (148 mg, 0.439 mmol) in MeOH (3 mL) and 1 M aqueous NaOH (5 ml) was stirred at 0 ° C for 5 minutes and at room temperature for 2 hours. The mixture was neutralized with 1 M aqueous HCl at 0 ° C. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to give the title compound (69 mg, yield 59%) as a bright red solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 4.70 (1H, s), 6.65 (1H, d, J = 7.9 Hz), 7.76-7.92 (2H, m) , 7.99-8.17 (2H, m), 8.93 (1H, d, J = 7.9 Hz).

Reference example 116

3- (Hydroxymethyl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0703]

<img file="PL2393360T3_D0120.tif" />

[0704] To a solution of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (2.00 g, 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 stirred at -78 ° C for 1 hour, gradually warmed to room temperature, stirred at room temperature for 18 hours, diluted with 1 M aqueous HCl at 0 ° C, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30) to give the title compound (509 mg, 28% yield) as light yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 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), 8.08.16.16 (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-dihydro-pyridazine-3-carbaldehyde

171 [0705]

<img file="PL2393360T3_D0121.tif" />

[0706] To a solution of oxalyl chloride (0.175 mL, 2.07 mmol) in THF (7.5 mL) was added DMSO (0.294 mL, 4.14 mmol) at -78 ° C. A solution of 3 (hydroxymethyl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (509 mg, 1.88 mmol) in THF (7.5 mL) was added to the suspension at -78 ° C. . The suspension was stirred at -78 ° C for 1 hour. Et3N (1.05 mL, 7.52 mmol) was added to the mixture at -78 ° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 18 hours, diluted with 1 M aqueous HCl, extracted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (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. A mixture of the above residue in THF (9.5 mL) was added to the suspension at -78 ° C. The suspension was stirred at -78 ° C for 2 hours. Et3N (3.14 mL, 22.6 mmol) was added to the mixture at -78 ° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 17 hours, diluted with 1 M aqueous HCl, extracted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to obtain the title compound (257 mg, 51% yield) as a yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J = 8.2 Hz), 7.81-7.91 (2H, m), 8.08-8.15 ( 1H, m), 8.16 (1H, s), 8.98 (1H, d, J = 8.0 Hz), 10.07 (1H, s).

Reference example 118

5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylic acid

172 [0707]

<img file="PL2393360T3_D0122.tif" />

[0708] To a suspension of methyl 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (10.0 g, 30.5 mmol) in MeOH (100 mL) was added 1 M aqueous NaOH (61 ml) at 0 ° C. The mixture was stirred at room temperature for 30 minutes. To the solution, 1 M aqueous HCl (61 mL) was added at 0 ° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried under vacuum at 60 ° C to obtain the title compound (8.78 g, 92% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.98 (3H, s), 7.82-8.01 (2H, m), 8.11-8.34 (2H, m), 8, 97 (IH, s), 15.00 (IH, brs).

Reference example 119

3-Amino-5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0709]

<img file="PL2393360T3_D0123.tif" />

[0710] A mixture of 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylic acid (6.00 g, 19.1 mmol), DPPA (6.16 ml, 28.6 mmol) and Et3N (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated to 100 ° C for 2 hours. To the mixture, an 8 M aqueous NaOH solution (23.8 mL) was added at 0 ° C. The mixture was stirred at room temperature for 3 hours, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc / i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and recrystallized from EtOAc / hexane to give the title compound (3.57 g, 66% yield) as a pale yellow body DC:¹1 H NMR

173 (DMSO-d6, 300 MHz): δ ppm 3.83 (3H, s), 6.31 (2H, s), 7.64-7.79 (2H, m), 8.13 (2H, s) , 8.64 (IH, s).

Reference example 120

(2-phenyl-furan-3-yl) boronic acid [0711]

<img file="PL2393360T3_D0124.tif" />

[0712] To a mixture of 3-bromo-2-phenylfuran (6.70 g, 30.0 mmol) and B (Oi-Pr) 3 (10.4 mL, 45.0 mmol) in THF (67 mL) was added n -BuLi (1.65 M in hexane, 36.4 ml, 60 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes and at 0 ° C for 30 minutes. The mixture was diluted with 1 M aqueous HCl at 0 ° C, extracted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered, concentrated in vacuo and triturated with EtOAc / hexane to give the title compound (2.23 g, 40% yield) as a green solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.64 (1H, d, J = 1.4 Hz), 7.21-7.45 (3H, m), 7.69 (1H, d, J = 1.6 Hz), 8.00-8.08 (2H, m).

Reference example 121

(2-phenylthiophen-3-yl) boronic acid [0713]

<img file="PL2393360T3_D0125.tif" />

[0714] To a mixture of 3-bromo-2-phenylthiophene (1.99 g, 8.32 mmol) and B (Oi-Pr) 3 (1.81 ml, 12.5 mmol) in THF (20 ml) was added n -BuLi (1.65 M in hexane, 10.1 mL, 16.6 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes and at 0 ° C for 30 minutes. The mixture was diluted with 1 M aqueous HCl at 0 ° C, extracted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 90 / 10 to 0/100) to obtain the title compound (87.4 mg, 5% yield) as white

174 solid body: ¹H NMR (DMSO-d6, 300MHz): δ ppm 7.19 (1H, d, J = 4.9 Hz), 7.27-7.44 (3H, m), 7.46-7.58 (3H , m), 8.06 (2H, s).

Reference example 122

Methyl 4-methoxy-3-oxo-2- (pyridin-4-ylhydrazone) [0715]

<img file="PL2393360T3_D0126.tif" />

[0716] 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 nitrate (3.2 g, 46 mmol) was added portionwise to the mixture at -6 ° C and then crushed ice (approx. 25 g) was added to the solution. After stirring at -6 ° C for 10 minutes, the mixture was poured into a suspension of methyl 4-methoxyacetoacetate (5.0 mL, 38 mmol) and sodium acetate (44 g, 540 mmol) in MeOH (100 mL) at 0 ° C . The mixture was partitioned between AcOEt and water. The aqueous layer was extracted with AcOEt. The combined organic extracts were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residual solid was washed with AcOEt / hexane (1/3) to give the title compound (1.8 g, 19% yield) as a yellow solid:¹H NMR (300 MHz, CDCl3): δ ppm 3.48-3.53 (3H, m), 3.893,95 (3H, m), 4.64-4.69 (2H, m), 7.17- 7.34 (2H, m), 8.54-8.60 (2H, m), 12.65 (1H, brs).

Reference example 123

Methyl 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylate [0717]

<img file="PL2393360T3_D0127.tif" />

[0718] A mixture of methyl 4-methoxy-3-oxo-2- (pyridin-4-ylhydrazone) butanoate (18 g, 70 mmol) and N, N-dimethylformamide dimethyl acetal (28 mL, 210 mmol) in toluene (210 mL ) was heated under reflux for 4 hours. The mixture was concentrated under reduced pressure to give black crystals. The crystals were washed with 2-propanol / AcOEt (1: 4) to obtain the title compound (8.2 g, 45% yield) as pale yellow crystals:¹H NMR (300 MHz,

175

CDCl3): δ ppm 3.99 (3H, s), 4.00 (3H, s), 7.62 (2H, dd, J = 4.5, 1.5 Hz), 8.01 (1H, s ), 8.79 (2H, dd, J = 4.5, 1.5 Hz).

Reference example 124

5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylic acid [0719]

<img file="PL2393360T3_D0128.tif" />

[0720] To a solution of methyl 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylate (0.50 g, 1.9 mmol) in MeOH (10 mL) and THF (10 ml) 1 M aq. NaOH (3.0 ml, 3.0 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. A 1 M aqueous HCl solution (3.1 mL) was added to the residue. The formed precipitate was collected by filtration, washed with water and dried to give the title compound (0.47 g, 99% yield) as an off-white solid: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H, s), 7.97 (2H, dd, J = 4.7, 1.7 Hz), 8.83 (2H, dd, J = 4.7, 1.7 Hz), 8.92 (1H, s), 14.63 (1H, brs).

Reference example 125

N, 5-Dimethoxy-N-methyl-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxamide [0721]

<img file="PL2393360T3_D0129.tif" />

[0722] For 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 (9.5 g, 50 mmol) in DMF (160 mL) N, O-dimethylhydroxylamine hydrochloride (6.5 g, 66 mmol) and TEA (14 mL, 100 mmol) were added and the mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure. The residue was diluted with water, saturated with K2CO3 and extracted with AcOEt. (There were three layers.) The highest organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The intermediate layer was extracted with

176

CH2Cl2 (50 mL x 4) and the combined extracts dried over MgSO4, filtered and concentrated under reduced pressure. The two residues were combined and chromatographed on basic silica gel (0 / 100-10 / 90 MeOH / AcOEt) to give the title compound (9.6 g, 100% yield) as a pale yellow oil:¹H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.68 (3H, s), 3.98 (3H, s), 7.61 (2H, dd, J = 4, 8, 1.5 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-yl-pyridazin-4 (1H) -one [0723]

<img file="PL2393360T3_D0130.tif" />

[0724] To a solution of N, 5-dimethoxy-N-methyl-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxamide (9.6 g, 33 mmol) in THF (100 mL) was added dropwise 1 M MeMgBr in THF (66 mL, 66 mmol) at -78 ° C for 15 minutes. After stirring at -78 ° C for 1 hour, the mixture was quenched with 1 M aqueous HCl (70 mL). The mixture was warmed to room temperature, basified with 1 M aqueous NaOH, washed with AcOEt. The aqueous layer was extracted with CH2Cl2 (50 mL × 4). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to obtain the title compound (2.1 g, 26% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ 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).

Reference example 127

Methyl 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylate [0725]

<img file="PL2393360T3_D0131.tif" />

[0726] To a suspension of quinoline-8-amine (10.0 g, 69.4 mmol) in 6M aqueous HCl (69.4 mL) was added a solution of NaNO2 (5.74 g, 83.2 mmol) in water ( 13.9 ml) in

177 at 0 ° C. To the suspension of methyl 4-methoxy-3-oxobutanoate (8.98 mL, 69.4 mmol) and NaOAc (104 g) in EtOH (118 mL) was added the above solution at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes. The precipitates were collected by filtration, washed with water and EtOAc and dried. N, N-Dimethylformamide dimethyl acetal (255 mL) was added to the solid at room temperature. The mixture was heated to reflux for 2.5 hours and cooled to room temperature. The precipitates were collected by filtration, washed with hexane and dried to give the title compound (16.6 g, 77% yield) as a gray solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.77 (3H, s), 3.80 (3H, s), 7.72 (1H, dd, J = 8.5, 4.0 Hz) , 7.81 (1H, t, J = 7.9 Hz), 8.09 (1H, d, J = 7.2 Hz), 8.25 (1H, d, J = 8.3 Hz), 8 , 58 (1H, s), 8.65 (1H, s), 8.97-9.04 (1H, m).

Reference example 128

5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylic acid [0727]

<img file="PL2393360T3_D0132.tif" />

[0728] 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) was added 1 M aqueous NaOH solution (64 ml) and THF (64 ml) at 0 ° C. The mixture was heated to 80 ° C. The homogeneous mixture was cooled to 0 ° C. To the mixture, 1 M aqueous HCl (64 mL) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried under vacuum at 60 ° C to give the title compound (3.59 g, 75% yield) as a fresh solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 7.73 (1H, dd, J = 8.4, 4.3 Hz), 7.81-7.89 ( 1H, m), 8.12 (1H, dd, J = 7.4, 1.4 Hz), 8.30 (1H, dd, J = 8.4, 1.2 Hz), 8.61 (1H , dd, J = 8.5, 1.6 Hz), 8.96-9.05 (2H, m).

Reference example 129

3-Amino-5-methoxy-1-quinolin-8-yl-pyridazin-4 (1H) -one [0729]

178

<img file="PL2393360T3_D0133.tif" />

[0730] A mixture of 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylic acid (2.59 g, 8.71 mmol), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol) in toluene (26 mL) was heated to reflux for 1 hour. DMF (52 ml), DPPA (2.81 ml, 13.1 mmol) and Et3N (1.82 ml, 13.1 mmol) were added to the suspension at room temperature. The mixture was heated to 100 ° C for 1.5 hours. To the mixture, an 8 M aqueous NaOH solution (10.9 mL) was added at 0 ° C. The mixture was stirred at room temperature for 1.5 hours, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 80/20) and on silica gel (EtOAc / MeOH = 100/0 to 50/50) and triturated with EtOAc / hexane to give the title compound (479 mg, 20% yield) as a pale yellow body DC: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.75 (3H, s), 6.11 (2H, s), 7.67 (1H, dd, J = 8.5, 4.4 Hz) , 7.72-7.80 (1H, m), 7.99 (1H, dd, J = 7.6, 1.5 Hz), 8.12 (1H, dd, J = 8.3, 1, 1 Hz), 8.48-8.61 (2H, m), 8.99 (1H, dd, J = 4.4, 1.7 Hz).

Reference example 130

3-Bromo-5-methoxy-1-quinolin-8-yl-pyridazin-4 (1H) -one [0731]

<img file="PL2393360T3_D0134.tif" />

[0732] To DMF (3 ml) isoamyl nitrate (0.387 ml, 2.91 mmol) and CuBr2 (299 mg, 1.34 mmol) were added at 0 ° C. A solution of 3-amino-5-methoxy-1-quinolin-8-yl-pyridazin-4 (1H) -one (300 mg, 1.12 mmol) in DMF (3 mL) was added to the mixture at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at 60 ° C for 2.5 hours. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over MgSO 4, filtered, concentrated in vacuo, purified by column chromatography

179 on basic silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30) and triturated with EtOAc / hexane to give the title compound (148 mg, 41% yield) as light yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.78 (3H, s), 7.72 (1H, dd, J = 8.3, 4.2 Hz), 7.82 (1H, t, J = 8.0 Hz), 8.10 (1H, d, J = 7.2 Hz), 8.25 (1H, d, J = 8.3 Hz), 8.59 (1H, dd, J = 8.3, 1.5 Hz), 8.73 (1H, s), 9.01 (1H, dd, J = 4.2, 1.5 Hz).

Reference example 131

(1-phenyl-1H-pyrazol-5-yl) boronic acid [0733]

<img file="PL2393360T3_D0135.tif" />

[0734] To a solution of 1-phenyl-1H-pyrazole (12.8 g, 88.9 mmol) in THF (355 mL) was added dropwise n-BuLi (1.63 M solution in hexane, 57.2 mL, 93, 3 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 1 hour. To the mixture, B (Oi-Pr) 3 (82.0 mL, 355 mmol) was added at -78 ° C. The mixture was stirred at -78 ° C for 1 hour, gradually warmed to room temperature and stirred at room temperature overnight. The pH of the mixture was adjusted to 5 with 1 M aqueous HCl. The mixture was concentrated in vacuo, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and crystallized from MeOH / EtOAc / hexane to give the title compound (12.6 g, 76% yield) as a pale yellow solid :¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.73 (1H, brs), 7.28-7.39 (1H, m), 7.39-7.54 (4H, m), 7, 66 (IH, s).

Reference example 132

1-Phenyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole [0735]

<img file="PL2393360T3_D0136.tif" />

[0736] To a mixture of (1-phenyl-1H-pyrazol-5-yl) boronic acid (8.57 g, 45.6 mmol) in toluene (86 ml) was added pinacol (5.39 g, 45.6 mmol) in room temperature. The mixture was heated to 40 ° C for 2 days. The mixture was concentrated under

180 in vacuo and triturated with hexane to give the title compound (7.93 g, 64% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 1.23 (12H, s), 6.84 (1H, s), 7.34-7.59 (5H, m), 7.75 (1H, d, J = 1.9 Hz).

Reference example 133

Methyl 1- (2,2-Difluoro-1,3-benzodioxol-4-yl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0737]

<img file="PL2393360T3_D0137.tif" />

[0738] A solution of sodium nitrite (1.4 g, 21 mmol) in H2O (10 mL) was added dropwise to a solution of 2,2-difluoro-1,3-benzodioxole-4-amine (3.0 g, 17 mmol) in 6M aqueous HCl (18 mL, 108 mmol) at 0 ° C. After stirring for 15 minutes at 0 ° C, the mixture was added to a suspension of methyl 4-methoxyacetoacetate (2.2 mL, 17 mmol) and sodium acetate (9.0 g, 110 mmol) in MeOH (40 mL) pre-cooled at 0 ° C. The mixture was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure.

[0739] A solution of the residue in N, N-dimethylformamide dimethyl acetal (20 mL, 150 mmol) was refluxed at reflux for 3 hours. The mixture was concentrated under reduced pressure. The remaining solid was washed with AcOEt / hexane (1/3) to give the title compound (4.1 g, 71% yield) as an orange solid:¹H NMR (300 MHz, CDCl3): δ ppm 3.96 (3H, s), 3.99 (3H, s), 7.15 (1H, dd, J = 8.0, 1.1 Hz), 7 , 23-7.30 (1H, m), 7.56 (1H, dd, J = 8.5, 1.1 Hz), 8.01 (1H, s).

Reference example 134

1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid [0740]

<img file="PL2393360T3_D0138.tif" />

181 [0741] To a solution of methyl 1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 12 mmol) in THF (100 mL) and MeOH (50 mL) 1 M aqueous NaOH (18 mL, 18 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and acidified with 1 M aqueous HCl. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound (3.8 g, 97% yield) as a yellow amorphous solid: ¹H NMR (300 MHz, CDCl3): δ ppm 4.06 (3H, s), 7.22-7.26 (1H, m), 7.34 (1H, t, J = 8.3 Hz), 7 , 72 (1H, dd, J = 8.3, 1.1 Hz), 8.29 (1H, s).

Reference example 135

1- (2,2-Difluoro-1,3-benzodioxol-4-yl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0742]

<img file="PL2393360T3_D0139.tif" />

[0743] To a mixture of 1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 12 mmol) , HOBt (2.7 g, 17 mmol) and WSC (3.4 g, 17 mmol) in DMF (50 ml) N, Odimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) and Et3N (4.9 ml, 35 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give orange crystals. The crystals were washed with AcOEt / hexane (1/4) to obtain the title compound (2.7 g, 62% yield) as pale yellow crystals:¹H NMR (300 MHz, CDCl3): δ 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 Hz), 7.57 (1H, dd, J = 8.7, 1.1 Hz), 8.06 (1H, s).

Reference example 136

3-Acetyl-1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxy-pyridazin-4 (1H) -one

182 [0744]

<img file="PL2393360T3_D0140.tif" />

[0745] 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 (2.7 g, 7.2 mmol) in THF (70 ml) was added dropwise with 1 M MeMgBr in THF (14 ml, 14 mmol) at -78 ° C for 15 minutes. After stirring at -78 ° C for 1 hour, the mixture was quenched with 1 M aqueous HCl (30 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g, 99% yield) as yellow crystals: ¹H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.95 (3H, s), 7.17 (1H, dd, J = 7.9, 1.1 Hz), 7 , 26-7.32 (1H, m), 7.55 (1H, dd, J = 8.7, 1.1 Hz), 8.00 (1H, s).

Reference example 137

1- (2,2-Difluoro-1,3-benzodioxol-4-yl) -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazin-4 (1H) -one [0746]

<img file="PL2393360T3_D0141.tif" />

[0747] A solution of 3-acetyl-1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxypyridazin 4 (1H) -one (2.3 g, 7.1 mmol) in dimethyl acetal N, N-dimethylformamide (75 ml) was heated to reflux for 3 hours. The mixture was concentrated under reduced pressure. The brown crystals were washed with AcOEt / hexane (1/1) to give the title compound (2.0 g, 74% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.94 (3H, s), 5.78 (1H, d, J = 11, 7 Hz), 7.10 (1H, dd, J = 8.3, 1.1 Hz), 7.23 (1H, t, J = 8.3 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.79 (1H, brs), 8.03 (1H, s).

Reference example 138

4- (Benzyloxy) -2-fluoroaniline [0748]

183

<img file="PL2393360T3_D0142.tif" />

[0749] A suspension of 3-fluoro-4-nitrophenol (6.28 g, 40 mmol), benzyl bromide (5.00 mL, 42 mmol) and K2CO3 (6.63 g, 48 mmol) in acetone (80 mL) was heated under reflux condenser at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give 4- (benzyloxy) 2-fluoro-1-nitrobenzene (16.0 g, 92% yield) as a pale yellow solid.

[0750] A solution of Na2S2O4 (34.8 g, 200 mmol) in H2O (200 mL) was added to a mixture of 4 (benzyloxy) -2-fluoro-1-nitrobenzene (16.0 g, 64.7 mmol), THF (150 ml) and EtOH (150 ml) and the mixture was stirred for 30 minutes 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 4 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 (5.84 g, 42% yield) as a light brown oil: ¹H NMR (300 MHz,

<img file="PL2393360T3_D0143.tif" />

(2H, m), 7.28-7.43 (5H, m).

Reference example 139

Methyl 2 - {[4- (Benzyloxy) -2-fluorophenyl] hydrazono} -4-methoxy-3-oxobutanoate [0751] [0752] A solution of NaNO2 (2.07 g, 30 mmol) in H2O (5 mL) was added dropwise at 0 ° C to a mixture of 4- (benzyloxy) -2-fluoroaniline (5.43 g, 25 mmol) and 6 M aqueous HCl (25 mL, 150 mmol). After stirring for 15 minutes, 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. A mixture of

184 the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give the title compound (8.48 g, 91% yield) as a yellow solid:¹H NMR (300 MHz, CDCl3): δ ppm 3.500 (3H χ 0.46, s), 3.502 (3H χ 0.54, s), 3.88 (3H χ 0.54, s), 3.92 ( 3H χ 0.46, s), 4.65 (2H χ 0.46, s), 4.68 (2H χ 0.54, s), 5.06 (2H χ 0.54, s), 5, 07 (2H χ 0.46, s), 6.75-6.86 (2H, m), 7.32-7.44 (5H, m), 7.53 (1H χ 0.46, t, J = 9.0 Hz), 7.76 (1H χ 0.54, t, J = 9.0 Hz), 13.12 (1H χ 0.46, brs), 15.13 (1H χ 0.54, br s).

Reference example 140

Methyl 1- [4- (Benzyloxy) -2-fluoro-phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0753]

<img file="PL2393360T3_D0144.tif" />

[0754] A solution of methyl 2 - {[4- (benzyloxy) -2-fluorophenyl] hydrazone} -4-methoxy-3oxobutanoate (8.46 g, 22.6 mmol) in N, N-dimethylformamide dimethyl acetal (80 mL) was heated under reflux condenser at reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with THF and recrystallized from hexane / THF to give the title compound (8.12 g, 93% yield) as a white solid: m.p. 143-144 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 3.96 (3H, s), 5.12 (2H, s), 6.83-6.91 (2H, m) , 7.33-7.44 (5H, m), 7.48-7.54 (1H, m), 7.69 (1H, d, J = 2.3 Hz). Anal. calc. for C20H17FN2O5: C, 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-1,4dihydropirydazyno-3-carboxamide

185 [0755]

<img file="PL2393360T3_D0145.tif" />

[0756] To a solution of N, O-dimethylhydroxylamine hydrochloride (5.27 g, 54 mmol) and iPr2NEt (9.41 mL, 54 mmol) in CH2Cl2 (50 mL) was slowly added AlMe3 (1.8 M solution in toluene, ml, 54 mmol) at 0 ° C under an atmosphere of Ar. After stirring for 1 hour, a solution of methyl 1- [4- (benzyloxy) -2-fluorophenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.07 g, 21 mmol) in CH 2 Cl 2 was added slowly. (50 ml) and the mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue 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:¹H NMR (300 MHz, CDCl3): δ 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 ).

Reference example 142

3-Acetyl-1- [4- (benzyloxy) -2-fluorophenyl] -5-methoxypyridazin-4 (1H) -one [0757]

<img file="PL2393360T3_D0146.tif" />

[0758] MeMgBr (1 M solution in THF, 56.4 mL, 56.4 mmol) was added dropwise at -78 ° C to a solution of 1- [4- (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 hour, the reaction mixture was quenched with 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a

186 with AcOEt and crystallized from hexane / AcOEt to give the title compound (5.86 g, 85% yield) as a pale yellow solid: m.p. 101-103 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.89 (3H, s), 5.13 (2H, s), 6.84-6.93 (2H, m) , 7.34-7.44 (5H, m), 7.48-7.55 (1H, m), 7.69 (1H, d, J = 2.3 Hz). Anal. calc. for C20H17FN2O4: C, 65.21; H, 4.65; N, 7.60. Found: C, 65.37; H, 4.68; N, 7.47.

Reference example 143

2-Fluoro-4- (trifluoromethoxy) aniline [0759]

<img file="PL2393360T3_D0147.tif" />

OCF₃ [0760] A mixture of 4-bromo-3-fluoro (trifluoromethoxy) benzene (6.6 g, 26 mmol), benzophenoneimine (6.4 ml, 38 mmol), Pd2 (dba) 3 (0.58 g, 0.64 mmol), Xantphos (1.5 g, 2.6 mmol) and sodium tert-butoxide (3.7 g, 38 mmol) in 1,4-dioxane (120 ml) were stirred at 100 ° C under N2 for 5 hours. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (0 / 100-5 / 95 AcOEt / hexane) to give a yellow oil. The residual oil was dissolved in THF (150 mL), and 1M aqueous HCl (50 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was basified with 8 M aqueous NaOH and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (0 / 100-5 / 95 AcOEt / hexane) to obtain the title compound (4.2 g, 85% yield) as a pale yellow oil:¹H NMR (300 MHz, DMSO-d6): δ ppm 5.36 (2H, s), 6.75-6.85 (1H, 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] hydrazone} -4-methoxy-3-oxobutanoate [0761]

187

<img file="PL2393360T3_D0148.tif" />

[0762] A solution of sodium nitrite (1.9 g, 28 mmol) in H2O (10 mL) was added dropwise to a solution of 2-fluoro-4- (trifluoromethoxy) aniline (4.6 g, 24 mmol) in 6 M HCl (24 mL, 144 mmol) at 0 ° C. After stirring for 15 minutes at 0 ° C, the mixture was added to a suspension of methyl 4-methoxyacetoacetate (3.1 mL, 24 mmol) and sodium acetate (12 g, 144 mmol) in MeOH (50 mL) pre-cooled at 0 ° C. The formed precipitate was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (4.8 g, 58% yield) as yellow crystals: ¹H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.94 (3H, s), 4.65 (2H, s), 7.06-7.14 (2H, m) , 7.59-7.68 (1H, m), 12.98 (1H, brs).

Reference example 145

Methyl 1- [2-Fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0763]

<img file="PL2393360T3_D0149.tif" />

[0764] A solution of methyl 2 - {[2-fluoro-4- (trifluoromethoxy) phenyl] hydrazone} -4-methoxy-3-oxobutanoate (3.8 g, 11 mmol) and N, N-dimethylformamide diisopropyl acetal (9.5 mL, 54 mmol) in toluene (60 ml) was refluxed for 5 hours. The mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (10 / 90-100 / 0 AcOEt / hexane) to obtain the title compound (3.4 g, 86% yield) as pale yellow crystals: ¹H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.17-7.25 (2H, m), 7.68-7.76 ( 2H, m).

188

Reference example 146

1- [2-Fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid [0765]

<img file="PL2393360T3_D0150.tif" />

OCF₃ [0766] For a solution of methyl 1- [2-fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (3.4 g, 9.3 mmol) in THF ( 150 ml) 1 M aqueous NaOH (14 ml, 14 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1 M aqueous HCl and concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound (3.2 g, 97% yield) as a pale yellow amorphous solid: ¹H NMR (300 MHz, DMSO-d6): δ 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, 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 [0767]

<img file="PL2393360T3_D0151.tif" />

[0768] For a mixture of 1- [2-fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 11 mmol), HOBt (2, 5 g, 16 mmol) and WSC (3.1 g, 16 mmol) in DMF (50 mL) N, Odimethylhydroxylamine hydrochloride (2.1 g, 22 mmol) and Et3N (4.5 mL, 32 mmol) were added and the mixture stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure.

189 [0769] To a solution of the residue in THF (100 mL) was added dropwise 1 M MeMgBr in THF (18 mL, 18 mmol) at -78 ° C for 15 minutes. After stirring at -78 ° C for 1 hour, the mixture was quenched with 1 M aqueous HCl (50 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.8 g, 75% yield) as a yellow oil: ¹H NMR (300 MHz, CDCl3): δ 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 [0770]

<img file="PL2393360T3_D0152.tif" />

[0771] To a solution of tert-butyl (3-bromo-2-fluorophenyl) 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 hours and concentrated in vacuo. The residue was diluted with 6 M aqueous HCl (62 mL). A solution of NaNO2 (2.06 g, 29.9 mmol) in water (5 mL) was added to the suspension at 0 ° C. To the 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 minutes. The precipitates were collected by filtration, diluted with EtOAc, washed with aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.36 g, 62% yield) as a brown solid:¹H NMR (DMSO-d6, 300 MHz): δ 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).

Reference example 149

Methyl 1- (3-Bromo-2-fluoro-phenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0772]

190

<img file="PL2393360T3_D0153.tif" />

[0773] A mixture of methyl 2 - [(3-bromo-2-fluorophenyl) hydrazone] -4-methoxy-3-oxobutanoate (5.36 g, 15.4 mmol) in N, N-dimethylformamide dimethyl acetal (54 ml) heated to reflux for 2 hours and cooled to 0 ° C. The precipitates were collected by filtration, washed with hexane and dried to give the title compound (4.16 g, 75% yield) as a brown solid:¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.80 (3H, s), 3.83 (3H, s), 7.40 (1H, td, J = 8.1, 1.1 Hz) , 7.75-7.84 (1H, m), 7.94 (1H, ddd, J = 8.1, 6.4, 1.7 Hz), 8.60 (1H, d, J = 1, 9 Hz).

Reference example 150

1- (3-Bromo-2-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid [0774]

<img file="PL2393360T3_D0154.tif" />

[0775] For a suspension of methyl 1- (3-bromo-2-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.16 g, 11.7 mmol) in MeOH (46 ml) 1 M aqueous NaOH (23 mL) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour. To the solution, 1 M aqueous HCl (23 mL) was added at 0 ° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 50 ° C to obtain the title compound (3.76 g, 94% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.87 (3H, s), 7.43 (1H, td, J = 8.1, 1.5 Hz), 7.767.85 (1H, m) , 7.98 (1H, ddd, J = 8.0, 6.5, 1.3 Hz), 8.86 (1H, s), 14.84 (1H, brs).

Reference example 151

1- (3-Bromo-2-fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropirydazyno3-carboxamide

191 [0776]

<img file="PL2393360T3_D0155.tif" />

[0777] A mixture of 1- (3-bromo-2-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.76 g, 11.0 mmol) and CDI (1.95 g , 12.1 mmol) in THF (38 ml) was heated to 40 ° C for 2 hours. To the solution, N, O-dimethylhydroxylamine hydrochloride (1.60 g, 16.4 mmol) and i-Pr2NEt (2.86 mL, 16.4 mmol) were added at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and 1 M aqueous HCl, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by basic silica gel column chromatography (EtOAc / MeOH = 100/0 to 80/20) with obtaining the title compound (4.22 g,&gt; 99% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ 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, J = 8.2, 6.9, 1.5 Hz), 7.92 (1H, ddd, J = 8.0, 6, 3, 1.5 Hz), 8.58 (1H, s).

Reference example 152

3-Acetyl-1- (3-bromo-2-fluorophenyl) -5-methoxypyridazin-4 (1H) -one [0778]

<img file="PL2393360T3_D0156.tif" />

[0779] To a solution of 1- (3-bromo-2-fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.22 g, 10.9 mmol) in THF (218 mL) was added MeMgBr (1.0 M in THF, 16.4 mL, 16.4 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 2 hours. The reaction was quenched with saturated aqueous NH4Cl solution at -78 ° C. The mixture was diluted with aqueous NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (EtOAc / MeOH = 100/0 to 50/50) to give

192 the title compound (3.48 g, 93% yield) as a yellow solid: ¹H-NMR (DMSO-d6, 300 MHz): δ ppm 2.50 (3H, s), 3.80 (3H, s), 7.36-7.46 (1H, m), 7.77-7 , 85 (1H, m), 7.89-7.99 (1H, m), 8.57 (1H, d, J = 1.9 Hz).

Reference example 153

Methyl 4-methoxy-3-oxo-2 - [(2,2,6-trifluoro-1,3-benzodioxol-5-yl) hydrazone] butanoate [0780]

<img file="PL2393360T3_D0157.tif" />

[0781] To a suspension of 2,2,6-trifluoro-1,3-benzodioxole-5-amine (4.95 g, 25.9 mmol) in 6 M aqueous HCl (25.9 mL) was added NaNO2 solution (2 , 15 g, 31.1 mmol) in water (5.2 ml) at 0 ° C. To the suspension of methyl 4-methoxy-3-oxobutanoate (3.35 mL, 25.9 mmol) and NaOAc (38.9 g) in EtOH (44 mL) was added the above solution at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine and aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (6.31 g, 70% yield) as a red solid body: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.33 (3H, s), 3.82 (3H, s), 4.66 (2H, s), 7.57-7.92 (2H, m), 12.32 (IH, brs).

Reference example 154

Methyl 5-methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine-3-carboxylate [0782]

<img file="PL2393360T3_D0158.tif" />

193 [0783] A mixture of methyl 4-methoxy-3-oxo-2 - [(2,2,6-trifluoro-1,3-benzodioxol-5-yl) hydrazone] butanoate (6.31 g, 18.1 mmol) in dimethyl acetal N, N-dimethylformamide (63 ml) was heated to reflux for 2.5 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30) and basic silica gel (hexane / EtOAc = 50 / 50 to 0/100) to obtain the title compound (1.53 g, 24% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.82 (3H, s), 7.94 (1H, d, J = 9.4 Hz), 8.04 (1H, d, J = 6.4 Hz), 8.54 (1H, s).

Reference example 155

5-methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine-3-carboxylic acid [0784]

<img file="PL2393360T3_D0159.tif" />

[0785] For a suspension of methyl 5-methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine-3-carboxylate (1.53 g, 4 , 27 mmol) in MeOH (17 ml) 1M aqueous NaOH (8.5 ml) was added at 0 ° C. The mixture was stirred at room temperature for 30 minutes. 1M aqueous HCl (8.5 mL) was added to the mixture 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 obtain the title compound (1.18 g, 80% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 7.98 (1H, d, J = 9.4 Hz), 8.03 (1H, d, J = 6, 4 Hz), 8.79 (IH, s), 14.77 (IH, brs).

Reference example 156

3-Amino-5-methoxy-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) pyridazin-4 (1H) -one [0786]

194

<img file="PL2393360T3_D0160.tif" />

[0787] A mixture of 5-methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) 1,4-dihydropyridazine-3-carboxylic acid (1.18 g, 3 , 42 mmol), DPPA (1.10 mL, 5.13 mmol) and Et3N (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated to 100 ° C for 1 hour. An 8 M aqueous NaOH solution (4.3 mL) was added to the mixture at 0 ° C. The mixture was stirred at room temperature for 1 hour, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and recrystallized from EtOAc / hexane to obtain the title compound (704 mg, 65% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.73 (3H, s), 6.21 (2H, s), 7.85 (1H, d, J = 9.4 Hz), 7.90 (1H, d, J = 6.4 Hz), 8.33 (1H, s).

Reference example 157

3-Bromo-5-methoxy-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) pyridazin-4 (1H) -one [0788]

<img file="PL2393360T3_D0161.tif" />

[0789] To a mixture of isoamyl nitrate (0.22 mL, 1.65 mmol) and CuBr2 (0.17 g, 0.762 mmol) in DMF (2 mL) was added a mixture of 3-amino-5-methoxy-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) pyridazin-4 (1H) -one (200 mg, 0.635 mmol) in DMF (4 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at 60 ° C for 2 hours. The mixture was diluted with water and brine, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) to give the title compound (145 mg, performance

195

60%) as a light yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 7.93 (1H, d, J = 9.5 Hz), 8.02 (1H, d, J = 6, 4 Hz), 8.59 (1H, d, J = 1.5 Hz).

Reference example 158

Methyl 4-methoxy-3-oxo-2 - [(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) hydrazone] methyl butanoate [0790]

<img file="PL2393360T3_D0162.tif" />

[0791] To a suspension of 2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-amine (4.87 g, 20.2 mmol) in 6M aqueous HCl ( 20.2 ml) a solution of NaNO2 (1.67 g, 24.2 mmol) in water (4 ml) was added at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes. To the suspension of methyl 4-methoxy-3-oxobutanoate (2.61 mL, 20.2 mmol) and NaOAc (30.3 g) in EtOH (34 mL) was added the above solution at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to give the title compound (6.84 g, 85% yield) as a red solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.33 (3H, s), 3.82 (3H, s), 4.68 (2H, s), 7.66-7.93 (2H, m), 12.16 (IH, brs).

Reference example 159

Methyl 5-methoxy-4-oxo-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-dihydropyridazine-3-carboxylate [0792 ]

<img file="PL2393360T3_D0163.tif" />

196 [0793] A mixture of methyl 4-methoxy-3-oxo-2 - [(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) hydrazono] butanoate (6.84 g, 17.2 mmol) in N, N-dimethylformamide dimethyl acetal (68 ml) was heated to reflux for 2.5 hours. The mixture was concentrated in vacuo, diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30) and on basic silica gel (hexane / EtOAc = 80/20 to 0/100 and EtOAc / MeOH = 100/0 to 70/30) to obtain the title compound (2.58 g, yield 37 %) as a light yellow solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.83 (3H, s), 8.01 (1H, d, J = 10.2 Hz), 8.16 (1H, d, J = 7.2 Hz), 8.58 (1H, s).

Reference example 160

5-methoxy-4-oxo-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-dihydropyridazine-3-carboxylic acid [0794 ]

<img file="PL2393360T3_D0164.tif" />

[0795] For 5-methoxy-4-oxo-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-dihydropyridazine-3 solution methyl carboxylate (2.58 g, 6.31 mmol) in MeOH (26 mL) was added a 1 M aqueous solution of NaOH (13 mL) at 0 ° C. The mixture was stirred at room temperature for 90 minutes. A 1 M aqueous HCl solution (13 ml) was added to the mixture 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 give the title compound (2.33 g, 94% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.86 (3H, s), 8.06 (1H, d, J = 10.2 Hz), 8.17 (1H, d, J = 6, 8 Hz), 8.82 (IH, s), 14.66 (IH, brs).

197

Reference example 161

3-Amino-5-methoxy-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) pyridazine-4 (1H) -one [0796]

<img file="PL2393360T3_D0165.tif" />

[0797] A mixture of 5-methoxy-4-oxo-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-dihydropyridazine-3 acid -carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 mL, 8.86 mmol) and Et3N (1.23 mL, 8.86 mmol) in toluene (23 mL) heated to 100 ° C for 90 minutes. An 8 M aqueous NaOH solution (7.4 ml) was added to the mixture at 0 ° C. The mixture was stirred at room temperature for 2 hours, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and silica gel (hexane / EtOAc = 80/20 to 0/100) and triturated with EtOAc / hexane to give the title compound (1.12 g, 53% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ p pm 3.73 (3H, s), 6.24 (2H, s), 7.92 (1H, d, J = 10.5 Hz), 7, 99 (1H, d, J = 6.8 Hz), 8.37 (1H, d, J = 1.5 Hz).

Reference example 162

3-Bromo-5-methoxy-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) pyridazine-4 (1H) -one [0798]

<img file="PL2393360T3_D0166.tif" />

[0799] To a mixture of isoamyl nitrate (0.473 mL, 3.56 mmol) and CuBr2 (367 mg, 1.64 mmol) in DMF (5 mL) was added a mixture of 3-amino-5-methoxy-1- (2 , 2,3,3,7198 pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) pyridazin-4 (1H) -one (500 mg, 1.37 mmol) in DMF (2.5 ml ) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at 60 ° C for 2.5 hours. The mixture was diluted with water and brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100) and crystallized with EtOH / hexane to obtain the title compound (381 mg, 65% yield) as a white solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 8.02 (1H, d, J = 10.5 Hz), 8.14 (1H, d, J = 6, 8 Hz), 8.63 (IH, s).

Reference example 163

1- [2-Fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0800]

<img file="PL2393360T3_D0167.tif" />

[0801] A mixture of 1- (3-bromo-2-fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (500 mg, 1.29 mmol), 1-methyl -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (295 mg, 1.42 mmol), Na2CO3 (302 mg, 2.85 mmol) and Pd (PPh3) 4 (74.5 mg, 0.0645 mmol) in DME (11.4 mL) and water (2.9 mL) was heated to reflux for 15 hours under Ar. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by basic silica gel column chromatography (EtOAc / MeOH = 100/0 to 70/30) to give the title compound (345 mg, 69% yield) as a white solid: ¹H NMR (DMSO-d6, 300MHz): δ ppm 3.25 (3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.90 (3H, s), 7, 35-7.44 (1H, m), 7.50-7.59 (1H, m), 7.84-7.94 (1H, m), 7.97 (1H, s), 8.23 ​​( 1H, d, J = 2.5 Hz), 8.58 (1H, s).

199

Reference example 164

3-Acetyl-1- [2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazine 4 (1H) -one [0802]

<img file="PL2393360T3_D0168.tif" />

[0803] For a solution of 1- [2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3- carboxamide (345 mg, 0.890 mmol) in THF (100 mL) was added MeMgBr (1.0 M in THF, 2.67 mL, 2.67 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 100 minutes. The reaction was quenched with saturated aqueous NH4Cl solution at -78 ° C. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (EtOAc / MeOH = 100/0 to 70/30) to give the title compound (243 mg, 80% yield) in forms of a white solid: ¹H NMR (DMSO-d6, 300MHz): δ ppm 2.51 (3H, brs), 3.81 (3H, s), 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), 8.58 (1H, d, J = 1.9 Hz).

Reference example 165

Methyl 2 - [(2-Fluoro-5-iodophenyl) hydrazono] -4-methoxy-3-oxobutanoate [0804]

<img file="PL2393360T3_D0169.tif" />

[0805] To a suspension of 2-fluoro-5-iodoaniline (9.83 g, 41.5 mmol) in a 6 M aqueous solution of HCl (83.0 mL) was added a solution of NaNO2 (3.43 g, 49.8 mmol) in water (8.3 ml) at 0 ° C. To the suspension of methyl 4-methoxy-3-oxobutanoate (5.37 mL, 41.5 mmol) and NaOAc (124 g) in EtOH (70 mL) was added the above solution at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes. The sediments were collected with

200 filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to give the title compound (14.2 g, 87% yield) as a red solid: ¹H NMR (DMSO-d6, 300MHz): δ 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

Methyl 1- (2-Fluoro-5-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0806]

<img file="PL2393360T3_D0170.tif" />

[0807] A mixture of methyl 2 - [(2-fluoro-5-iodophenyl) hydrazone] -4-methoxy-3-oxobutanoate (14.2 g, 35.9 mmol) in N, N-dimethylformamide dimethyl acetal (142 ml) heated to reflux for 1.5 hours and cooled to 0 ° C. The precipitates were collected by filtration, washed with hexane and dried to give the title compound (11.3 g, 78% yield) as a pale yellow solid:¹H NMR (DMSO-d6, 300MHz): δ ppm 3.80 (3H, s), 3.82 (3H, s), 7.37 (1H, dd, J = 10.6, 8.7 Hz), 7.90-8.01 (1H, m), 8.14 (1H, dd, J = 7.2, 2.3 Hz), 8.55 (1H, s).

Reference example 167

1- (2-fluoro-5-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid [0808]

<img file="PL2393360T3_D0171.tif" />

To a suspension of methyl 1- (2-fluoro-5-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (11.3 g, 28.1 mmol) in MeOH (112 ml) 1 M aqueous NaOH (56 ml) was added at 0 ° C. The mixture was stirred at

201 room temperature for 90 minutes. A 1 M aqueous HCl solution (56 ml) was added to the mixture 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 give the title compound (9.96 g, 91% yield) as a yellow solid:¹H NMR (DMSO-d6, 300MHz): δ ppm 3.88 (3H, s), 7.42 (1H, dd, J = 10.6, 8.7 Hz), 8.00 (1H, ddd, J = 8.7, 4.5, 2.3 Hz), 8.16 (1H, dd, J = 7.2, 2.3 Hz), 8.85 (1H, s), 14.86 (1H, br s).

Reference example 168

1- (2-Fluoro-5-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0810]

<img file="PL2393360T3_D0172.tif" />

[0811] A mixture of 1- (2-fluoro-5-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (9.96 g, 25.5 mmol) and CDI (4.55 g , 28.1 mmol) in THF (200 ml) was heated to 40 ° C for 30 minutes and 50 ° C for 90 minutes. DMF (20 ml) was added to the mixture. The mixture was stirred at 50 ° C for 70 minutes. To the solution, N, O-dimethylhydroxylamine hydrochloride (3.74 g, 38.3 mmol) and i-Pr2NEt (6.67 mL, 38.3 mmol) were added at room temperature. The solution was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted with water and 1 M aqueous HCl, extracted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (hexane / EtOAc = 20/80 to 0/100 and EtOAc / MeOH = 100/0 to 0/100) and triturated with MeOH / EtOH / hexane to give the title compound (9.11 g, 82% yield) as a pale yellow solid : ¹H NMR (DMSO-d6, 300MHz, δ ppm 3.24 (3H, s), 3.56 (3H, s), 3.80 (3H, s), 7.36 (1H, dd, J = 10, 6, 8.7 Hz), 7.93 (1H, ddd, J = 8.7, 4.5, 2.3 Hz), 8.12 (1H, dd, J = 7.4, 2.1 Hz ), 8.53 (1H, s).

202

Reference example 169

1- [2-Fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0812]

<img file="PL2393360T3_D0173.tif" />

[0813] A mixture of 1- (2-fluoro-5-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (500 mg, 1.15 mmol), 1-methyl -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (264 mg, 1.27 mmol), Na2CO3 (268 mg, 2.53 mmol) and Pd (PPh3) 4 (66.4 mg, 0.0575 mmol) in DME (10.1 mL) and water (2.5 mL) was heated to reflux for 14 hours under Ar. The mixture was diluted with water, brine and saturated aqueous NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by basic silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 60/40) to obtain the title compound (267 mg, 60% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300MHz): δ ppm 3.25 (3H, s), 3.59 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 7, 51 (1H, dd, J = 10.4, 8.9 Hz), 7.73-7.80 (1H, m), 7.89-7.97 (2H, m), 8.23 ​​(1H, s), 8.58 (IH, s).

Reference example 170

3-Acetyl-1- [2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazine 4 (1H) -one [0814]

<img file="PL2393360T3_D0174.tif" />

[0815] For a mixture of 1- [2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxyN-methyl-4-oxo-1,4-dihydropyridazine-3- carboxamide (267 mg, 0.687 mmol) in THF

203 (80 ml) MeMgBr (1.0 M in THF, 2.06 ml, 2.06 mmol) was added at -78 ° C under N2. The mixture was stirred at -78 ° C for 2 hours. MeMgBr (1.0 M in THF, 0.687 mL, 0.687 mmol) was added to the mixture at -78 ° C. The mixture was stirred at -78 ° C for 1 hour. MeMgBr (1.0 M in THF, 1.37 mL, 1.37 mmol) was added to the mixture at -78 ° C. The mixture was stirred at -78 ° C for 3 hours. The reaction was quenched with saturated aqueous NH4Cl solution at -78 ° C. The mixture was diluted with saturated aqueous NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (EtOAc / MeOH = 100/0 to 70/30) to give the title compound ( 201 mg, 85% yield) as a yellow solid:¹H NMR (DMSO-d6, 300MHz): δ 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, J = 1.5 Hz).

Reference example 171

1- (difluoromethyl) -1H-pyrazole-4-boronic acid pinacol ester [0816]

<img file="PL2393360T3_D0175.tif" />

[0817] Suspension of 1H-pyrazole-4-boronic acid pinacolic ester (5.16 g, 26.6 mmol), CF2ClCO2Na (4.86 g, 31.9 mmol) and 18-crown-6 (1.41 g, 5.32 mmol) in CH3CN (100 mL) was heated to reflux for 20 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (3.03 g, 47% yield) as a yellow oil: ¹H NMR (300 MHz, CDCl3): δ ppm 1.33 (12H, s), 7.22 (1H, t, J = 60.7 Hz), 7.89 (1H, s), 8.13 (1H , s).

Reference example 172

Tert-butyl 1- {3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) yl] phenyl} hydrazinecarboxylate

204 [0818]

<img file="PL2393360T3_D0176.tif" />

Η₂Ν '^Νγ γ °;

[0819] Suspension 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (2.44 g, 5.0 mmol), tert-butyl carbazate (0.727 g, 5.5 mmol), CuI (0.0095 g, 0.05 mmol), 1,10-phenanthroline (0.072 g, 0.4 mmol) and Cs2CO3 (2.28 g, 7.0 mmol) in DMF (25 ml) was stirred for 5 hours at 100 ° C under an atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt three times. The combined extracts were washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and crystallized from hexane / AcOEt to give the title compound (2.04 g, 83% yield) as a pale yellow solid: m.p. 163-165 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 1.58 (9H, s), 3.90 (3H, s), 4.36 (2H, s), 6.31 (1H, t, J = 9, 0 Hz), 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. calc. for C25H25FN6O4: C, 60.97; H, 5.12; N, 17.06. Found: C, 61.20; H, 5.13; N, 16.81.

Reference example 173

3 - {[2- (1-Methylethyl) phenyl] hydrazone} pentane-2,4-dione [0820]

<img file="PL2393360T3_D0177.tif" />

[0821] 2- (1-Methylethyl) aniline (2.00 g, 14.81 mmol) was added to a solution of 12 ml phosphoric acid (85%) and 8 ml nitric acid (65%) at -6 ° C, and then sodium nitrate (1.23 g, 17.78 mmol) in 4 ml water at 0 ° C was added dropwise and the mixture was stirred at 0 ° C for 30 minutes. Then, a solution of potassium acetate (4.35 g, 44.43 mmol) and acetylacetone (1.92 g, 19.25 mmol) in 80 mL ethanol and 20 mL water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (0.98 g, 27% yield): ¹H NMR (400

205

MHz, CDCl3): δ ppm 1.34 (6H, d, J = 6.8 Hz), 2.52 (3H, s), 2.63 (3H, 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 174

2- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzonitrile [0822] ο ο

<img file="PL2393360T3_D0178.tif" />

[0823] 2-Aminobenzonitrile (5.00 g, 42.37 mmol) was added to a solution of 30 mL of phosphoric acid (85%) and 20 mL of nitric acid (65%) at -6 ° C, followed by the addition of nitrate ( III) sodium (3.50 g, 50.78 mmol) in 10 ml water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. Then, a solution of potassium acetate (12.45 g, 127.11 mmol) and acetylacetone (5.51 g, 55.08 mmol) in 80 ml ethanol and 48 ml water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (4.00 g, 41% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (3H, s), 2.63 (3H, s), 7.21-7.25 (1H,

m), 7.62-7.66 (2H, m), 7.77-7.79 (1H, m), 15.01 (1H, s).

Reference example 175

3- (Biphenyl-2-ylhydrazone) pentane-2,4-dione [0824] [0825] Biphenyl-2-amine (500 mg, 2.96 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C, then sodium nitrate (254 mg, 3.55 mmol) in 1 ml water at 0 ° C was added dropwise and the mixture was stirred at 0 ° C for 30 minutes. Then, a solution of potassium acetate (870 mg, 8.88 mmol) and acetylacetone (385 mg, 3.85 mmol) in 60 ml ethanol and 32 ml water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (420 mg, 51% yield):

206 ¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (3H, s), 2.52 (3H, s), 7.29-7.60 (9H, m), 14.63 (1H, s) .

Reference example 176

3 - [(2-Ethoxyphenyl) hydrazono] pentane-2,4-dione [0826]

<img file="PL2393360T3_D0179.tif" />

[0827] 2-Ethoxyaniline (2.00 g, 14.60 mmol) was added to a solution of 12 mL phosphoric acid (85%) and 8 mL nitric acid (65%) at -6 ° C, followed by the dropwise addition of nitrate ( III) sodium (1.21 g, 17.52 mmol) in 10 ml water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. Then, a solution of potassium acetate (4.29 g, 43.80 mmol) and acetylacetone (1.90 g, 18.98 mmol) in 60 mL ethanol and 25 mL water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (2.00 g, 55% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 1.57 (3H, t, J = 7.2 Hz), 2.53 (3H, s), 2.63 (3H, s), 4.20 (2H , t, J = 7.2 Hz), 7.03-7.07 (1H, m), 7.14-7.18 (1H, m), 7.74-7.84 (2H, m), 14.86 (IH, s).

Reference example 177

3 - {[2-1-Methylethoxy) phenyl] hydrazono} pentane-2,4-dione [0828]

<img file="PL2393360T3_D0180.tif" />

[0829] 2- (1-Methylethoxy) aniline (1.00 g, 6.62 mmol) was added to a solution of 6 ml of phosphoric acid (85%) and 4 ml of nitric acid (65%) at -6 ° C, and then sodium nitrate (0.55 g, 7.95 mmol) in 2 mL water at 0 ° C was added dropwise and the mixture was stirred at 0 ° C for 30 minutes. Then, a solution of potassium acetate (1.95 g, 19.86 mmol) and acetylacetone (0.86 g, 8.61 mmol) in 40 mL ethanol and 10 mL water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (0.53 g, 30% yield): ¹H NMR (400

207

MHz, CDCl3): δ ppm 1.28-1.41 (6H, m), 2.50 (3H, s), 2.63 (3H, s), 4.53-4.59 (1H, m) , 7.21-7.25 (1H, m), 7.62-7.66 (2H, m), 7.77-7.79 (1H, m), 15.01 (1H, s).

Reference example 178

3 - {[2- (Trifluoromethoxy) phenyl] hydrazono} pentane-2,4-dione [0830]

<img file="PL2393360T3_D0181.tif" />

[0831] 2- (Trifluoromethoxy) aniline (1.00 g, 5.64 mmol) was added to a solution of 6 ml of phosphoric acid (85%) and 4 ml of nitric acid (65%) at -6 ° C, followed by the addition of dropwise sodium nitrate (389 mg, 5.64 mmol, 1.0 eq) in 2 mL water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. A mixture of potassium acetate (1.66 g, 16.92 mmol) and acetylacetone (564 mg, 5.64 mmol) in 80 ml ethanol and 48 ml water was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (1.3 g, 80% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.54 (s, 3H), 2.65 (s, 3H), 7.20-7.24 (m, 1H), 7.33-7.42 ( m, 2H), 7.87 (dd, J = 8.4, 1.6 Hz, 1H), 14.86 (s, 1H).

Reference example 179

3 - [(2-Phenoxyphenyl) hydrazone] pentane-2,4-dione [0832]

<img file="PL2393360T3_D0182.tif" />

[0833] 2-Phenoxyaniline (2.00 g, 10.81 mmol) was added to a solution of 12 mL of phosphoric acid (85%) and 8 mL of nitric acid (65%) at -6 ° C, followed by the dropwise addition of nitrate ( III) sodium (0.90 g, 12.97 mmol) in 2 ml water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. Then, a mixture of potassium acetate (3.18 g, 32.43 mmol) and acetylacetone (1.40 g, 14.05 mmol) in 80 ml ethanol and 48 ml water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water,

208

EtOH / H2O (1/1) and hexane and dried to give the title compound (1.00 g, 31% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (3H, s), 2.63 (3H, s), 7.26-7.88 (9H, m), 14.91 (1H, s) .

Reference example 180

3 - {[2- (Methylsulfinyl) phenyl] hydrazono} pentane-2,4-dione [0834]

<img file="PL2393360T3_D0183.tif" />

[0835] 2- (Methylsulfinyl) aniline (0.50 g, 3.22 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C, followed by the addition of dropwise sodium nitrate (0.27 g, 3.87 mmol) in 2 ml water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. Then, a mixture of potassium acetate (0.95 g, 9.66 mmol) and acetylacetone (0.42 g, 4.19 mmol) in 80 ml ethanol and 48 ml water was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (0.66 g, 77% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.07 (3H, s), 2.55 (3H, s), 2.64 (3H, s), 7.29-7.87 (4H, m) , 15.06 (1H, s).

Reference example 181

3 - {[3- (Trifluoromethoxy) phenyl] hydrazono} pentane-2,4-dione [0836]

<img file="PL2393360T3_D0184.tif" />

[0837] 3- (Trifluoromethoxy) aniline (1.00 g, 5.64 mmol) was added to a solution of 6 mL phosphoric acid (85%) and 4 mL nitric acid (65%) at -6 ° C, followed by the addition of dropwise sodium nitrate (389 mg, 5.64 mmol) in 2 mL water at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. A mixture of potassium acetate (1.66 g, 16.92 mmol) and acetylacetone (564 mg, 5.64 mmol) in 80 ml ethanol and 48 ml water was then added dropwise to the reaction mixture. The mixture was stirred

209 at room temperature overnight, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (1.2 g, 74% yield): ¹H NMR (400 MHz, CDCl3): δ 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 (s, 1H).

Reference example 182

N- {4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] phenyl} acetamide [0838]

<img file="PL2393360T3_D0185.tif" />

Χ^ΝΗ [0839] N- (4-Aminophenyl) acetamide (1000 mg, 6.66 mmol) was added to a solution of 6 mL phosphoric acid (85%) and 4 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature, it was cooled to -6 ° C and solid sodium nitrate (460 mg, 6.66 mmol) was added over 10 minutes. A small piece of ice (50 g) was added to the solution. The mixture was added at 0 ° C to a suspension of 2.4-pentanedione (666 mg, 6.66 mmol) and potassium acetate (40 g) in ethanol (400 ml). The solution was stirred for 15 minutes and then added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1400 mg, 80% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.22 (3H, s), 2.48 (3H, s), 2.60 (3H, s), 7.22 (1H, brs), 7.38 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 14.84 (1H, s).

Reference example 183

3- {[4- (Dimethylamino) phenyl] hydrazono} pentane-2,4-dione [0840]

<img file="PL2393360T3_D0186.tif" />

[0841] N, N-Dimethylbenzene-1,4-diamine (500 mg, 3.67 mmol) was added to the solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6 ° C. When

210 the mixture reached room temperature, it was cooled to -6 ° C and sodium nitrate (253 mg, 3.67 mmol) was added over 10 minutes. A small piece of ice (50 g) was added to the solution. The mixture was added at 0 ° C to a suspension of 2.4-pentanedione (367 mg, 3.67 mmol) and potassium acetate (20 g) in ethanol (250 ml). The solution was stirred for 15 minutes and then added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (870 mg, 96% yield) as brown solid body: ¹H NMR (400 MHz, CDCl3): δ 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).

Reference example 184

3 - {[4- (4-Methylpiperazin-1-yl) phenyl] hydrazone} pentane-2,4-dione [0842] ο ο

<img file="PL2393360T3_D0187.tif" />

[0843] 4- (4-Methylpiperazin-1-yl) aniline (1000 mg, 5.24 mmol) was added to a solution of 6 mL phosphoric acid (85%) and 4 mL nitric acid (65%) at -6 ° C . When the mixture reached room temperature, it was cooled to -6 ° C and sodium nitrate (361 mg, 5.24 mmol) was added over 10 minutes. A small piece of ice (50 g) was added to the solution. The mixture was added at 0 ° C to a suspension of 2.4-pentanedione (524 mg, 5.24 mmol) and potassium acetate (30 g) in ethanol (400 ml). The solution was stirred for 15 minutes and then added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (610 mg, 39% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.40 (3H, s), 2.50 (3H, s), 2.62 (3H, s), 3.10 (4H, t, J = 5, 2 Hz), 3.25 (4H, t, J = 4.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 7.6 Hz ), 15.08 (IH, brs).

Reference example 185

3 - {[4- (1H-1,2,4-triazol-1-yl) phenyl] hydrazono} pentane-2,4-dione

211 [0844]

<img file="PL2393360T3_D0188.tif" />

[0845] 4- (1H-1,2,4-Triazol-1-yl) aniline (500 mg, 3.12 mmol) was added to a solution of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C. When the mixture reached room temperature, it was cooled to -6 ° C and sodium nitrate (216 mg, 3.12 mmol) was added over 10 minutes. A small piece of ice (50 g) was added to the solution. The mixture was added at 0 ° C to a suspension of 2.4-pentanedione (312 mg, 3.12 mmol) and potassium acetate (20 g) in ethanol (250 ml). The solution was stirred for 15 minutes and then added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (600 mg, 71% yield) as brown solid body: ¹H NMR (400 MHz, CDCl3): δ 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] hydrazono} pentane-2,4-dione [0846]

<img file="PL2393360T3_D0189.tif" />

[0847] 4- (Trifluoromethoxy) aniline (1.00 g, 6.9 mmol) was added to a solution of 6 ml of phosphoric acid (85%) and 4 ml of nitric acid (65%) at -6 ° C, followed by the addition of sodium nitrate (0.601 g, 8.7 mmol, 1.2 eq) in 10 ml water dropwise at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. A mixture of potassium acetate (2.028 g, 20.7 mmol, 3.0 eq) and acetylacetone (0.8 mL, 7.0 mmol, 1.0 eq) in 20 mL of ethanol was then added dropwise to the reaction mixture. The mixture was stirred at room temperature for 15 minutes, filtered,

212 extracted with AcOEt, washed with brine and dried to give the crude product (1.58 g, 88% yield) which was used directly in the next step. ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 3H), 2.61 (s, 3H), 7.26-7.28 (m, 2H), 7.40-7.43 ( m, 2H), 14.69 (s, 1H).

Reference example 187

3 - {[2-Fluoro-3- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione [0848]

<img file="PL2393360T3_D0190.tif" />

[0849] To a solution of 2-fluoro-3- (trifluoromethyl) aniline (1.0 g, 5.58 mmol) in 8 ml acetic acid and 1.3 ml concentrated hydrochloride solution, sodium (III) nitrate (462 mg) was added dropwise. , 6.69 mmol) in 2.1 ml water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (1.37 g, 16.8 mmol) and acetylacetone (726 mg, 7.26 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (900 mg, 55% yield). ¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.63 (s, 3H), 7.30-7.34 (m, 1H), 7.38-7.41 ( m, 1H), 7.94-7.96 (m, 1H), 14.66 (s, 1H).

Reference example 188

3 - [(2,3-Difluorophenyl) hydrazone] pentane-2,4-dione [0850]

<img file="PL2393360T3_D0191.tif" />

<img file="PL2393360T3_D0192.tif" />

F [0851] To a solution of 2,3-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL acetic acid and 1.69 mL concentrated hydrochloride solution, sodium nitrate (600 mg, 9 mg) was added dropwise. , 3 mmol) in 2.7 ml of water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. A mixture of sodium acetate (1.78 g, 21.7 mmol, 3.0 eq) and acetylacetone (1 g, 10 mmol, 1.3 eq) was then added dropwise to the reaction mixture.

213

The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (900 mg, 48% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.61 (s, 3H), 6.93-7.00 (m, 1H), 7.11-7.17 ( m, 1H), 7.50-7.56 (m, 1H), 14.64 (s, 1H).

Reference example 189

3 - [(2,2-Difluoro-1,3-benzodioxol-4-yl) hydrazone] pentane-2,4-dione [0852]

<img file="PL2393360T3_D0193.tif" />

[0853] A solution of sodium nitrate (III) (0.96 g, 14 mmol) in H2O (5 mL) was added dropwise to a solution of 2,2-difluoro-1,3-benzodioxole-4-amine (2.0 g, 12 mmol) in 6M aqueous HCl (12 mL, 72 mmol) at 0 ° C. After stirring for 15 minutes at 0 ° C, the mixture was added to a suspension of 2,4-pentanedione (1.2 mL, 12 mmol) and sodium acetate (5.9 g, 72 mmol) in MeOH (20 mL) pre-cooled in at 0 ° C. The formed precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 90% yield) as orange crystals:¹H NMR (300 MHz, CDCl3): δ ppm 2.49 (3H, s), 2.63 (3H, s), 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).

Reference example 190

3 - {[2-Fluoro-4- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione [0854]

<img file="PL2393360T3_D0194.tif" />

[0855] To a solution of 2-fluoro-4- (trifluoromethyl) aniline (1.0 g, 5.58 mmol) in 8 ml acetic acid and 1.3 ml concentrated hydrochloride solution, sodium (III) nitrate was added dropwise

214 (462 mg, 6.69 mmol) in 2.1 mL water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (1.37 g, 16.8 mmol, 3.0 equiv) and acetylacetone (726 mg, 7.26 mmol, 1.3 equiv) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (720 mg, 44% yield):¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.63 (s, 3H), 7.42-7.50 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 14.56 (s, 1H).

Reference Example 191 tert-butyl [4- (Difluoromethoxy) -2-fluorophenyl] carbamate [0856]

<img file="PL2393360T3_D0195.tif" />

OCHF₂ [0857] A solution of 4- (difluoromethoxy) -2-fluorobenzoic acid (1 g, 4.85 mmol), DPPA (1.6 g, 5.83 mmol) and Et3N (0.59 g, 5.83 mmol) in 16 ml of t-BuOH was refluxed for 4 hours and then concentrated. The residue was dissolved in dichloromethane (40 mL), washed with 1M aqueous HCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether / AcOEt = 4/1) to give the title compound (850 mg, 63% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl3): δ 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, 1H).

Reference example 192

3 - {[4- (Difluoromethoxy) -2-fluorophenyl] hydrazone} pentane-2,4-dione [0858]

<img file="PL2393360T3_D0196.tif" />

215 [0859] A solution of tert-butyl [4- (difluoromethoxy) -2-fluorophenyl] carbamate (850 mg, 3.07 mmol) in 300 mL HCl in AcOEt was stirred overnight and concentrated under reduced pressure.

[0860] To a solution of the residue in 5.5 ml acetic acid and 0.9 ml concentrated hydrochloride solution, sodium nitrate (239 mg, 3.39 mmol) in 1.4 ml water at 0 ° C was added dropwise. the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (703 mg, 8.47 mmol, 3.0 equiv) and acetylacetone (367 mg, 3.67 mmol, 1.3 equiv) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (300 mg, 37% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.62 (s, 3H), 6.51 (t, J = 72.8 Hz, 1H), 6.957.04 (m , 2H), 7.73-7.77 (m, 1H), 14.70 (s, 1H).

Reference example 193

2-Fluoro-4- (trifluoromethoxy) benzoic acid [0861]

<img file="PL2393360T3_D0197.tif" />

[0862] A solution of 1-bromo-2-fluoro-4- (trifluoromethoxy) benzene (8 g, 30.8 mmol) in 170 ml THF was cooled to -40 ° C and then i-PrMgBr (0.4 mol / 1 in THF, 91 ml). After stirring for 3 hours, CO2 was injected for 2 hours at 0 ° C. The mixture was washed with 1M aqueous HCl and separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with petroleum ether to obtain the title compound (6 g, 87% yield): ¹1 H NMR (400 MHz, CDCl 3): δ ppm 7.05-7.12 (m, 2H), 8.10 (t, J = 8.4 Hz, 1H).

Reference Example 194 tert-butyl [2-Fluoro-4- (trifluoromethoxy) phenyl] carbamate [0863]

NHBoc

<img file="PL2393360T3_D0198.tif" />

216 [0864] 2-fluoro-4- (trifluoromethoxy) benzoic acid solution (3 g, 13.4 mmol), DPPA (4.4 g, 16.1 mmol) and Et3N (1.63 g, 16.1 mmol) in 130 ml of t-BuOH was refluxed for 4 hours and then concentrated. The residue was dissolved in dichloromethane (200 mL), washed with 1M aqueous HCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether / AcOEt = 4/1) to give the title compound (2 g, 50% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl3): δ ppm 1.27 (s, 9H), 6.97-7.03 (m, 1H), 7.21-7.27 (m, 1H), 7.37- 7.41 (m, 1H).

Reference example 195

3 - {[2-Fluoro-4- (trifluoromethoxy) phenyl] hydrazone} pentane-2,4-dione [0865]

<img file="PL2393360T3_D0199.tif" />

[0866] A solution of tert-butyl [2-fluoro-4- (trifluoromethoxy) phenyl] carbamate (2 g, 6.8 mmol) in 300 mL HCl in AcOEt was stirred for 3 hours at 0 ° C and concentrated under reduced pressure.

[0867] To a solution of the residue in 20 mL of acetic acid and 3.5 mL of concentrated hydrochloride solution, sodium nitrate (507 mg, 7.34 mmol) in 5 mL of water at 0 ° C was added dropwise and the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (1.5 g, 18.3 mmol, 3.0 equiv) and acetylacetone (793 mg, 7.93 mmol, 1.3 equiv) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (920 mg, 50% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 3H), 2.63 (s, 3H), 7.08-7.13 (m, 2H), 7.78 (t, J = 8.8 Hz, 1H), 14.65 (s, 1H).

Reference example 196

3 - [(2,4-Difluorophenyl) hydrazone] pentane-2,4-dione [0868]

217

<img file="PL2393360T3_D0200.tif" />

F [0869] To a solution of 2,4-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 ml acetic acid and 1.69 ml concentrated hydrochloride solution, sodium (III) nitrate (600 mg, dropwise was added)

9.3 mmol) in 2.7 ml of water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. A mixture of sodium acetate (1.78 g, 21.7 mmol) and acetylacetone (1 g, 10 mmol) was then added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (550 mg, 30% yield):¹H NMR (400 MHz, CDCl3): δ ppm 2.48 (s, 3H), 2.61 (s, 3H), 6.91-7.00 (m, 2H), 7.70-7.76 ( m, 1H), 14.72 (s, 1H).

Reference example 197

3 - [(4-Chloro-2-fluorophenyl) hydrazono] pentane-2,4-dione [0870]

<img file="PL2393360T3_D0201.tif" />

Cf [0871] To a solution of 4-chloro-2-fluoroaniline (1 g, 6.87 mmol) in 9.8 ml acetic acid and 1.6 ml concentrated hydrochloride solution, sodium nitrate (III) (568 mg, 8 , 24 mmol) in 2.6 ml water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (1.69 g, 20.6 mmol) and acetylacetone (893 mg, 8.93 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1/1) and hexane and dried to give the title compound (1 g, 57% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.60 (s, 3H), 7.15-7.25 (m, 2H), 7.69 (t, J = 8.4 Hz, 1H), 14.64 (s, 1H).

Reference example 198

3- [2-Fluoro-5- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione [0872]

218

<img file="PL2393360T3_D0202.tif" />

[0873] 2-Fluoro-5- (trifluoromethyl) aniline (2.00 g, 15.6 mmol) was added to the solution to 15.6 mL HOAc and 2.6 mL concentrated HCl, stirred, and then added (III) nitrate sodium (0.925 g, 13.4 mmol) in 4 ml water at 0 ° C and the mixture was stirred at 0 ° C for 60 minutes. Then potassium acetate (3.28 g, 3.5 mmol) and acetylacetone (1.83 mL, 14.5 mmol) were added dropwise. The mixture was stirred at room temperature overnight and filtered. The residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.06 g, 64% yield): ¹H NMR (400 MHz, CDCl3): δ ppm 2.53 (s, 3H), 2.64 (s, 3H), 7.26-6.30 (m, 1H), 7.39-7.42 ( m, 1H), 7.99-8.01 (m, 1H), 14.62 (s, 1H).

Reference example 199

3 - [(2,5-Difluorophenyl) hydrazone] pentane-2,4-dione [0874]

<img file="PL2393360T3_D0203.tif" />

[0875] 2,5-Difluoroaniline (2.10 g, 15.5 mmol) was added to the solution 21.6 mL HOAc and 3.6 mL concentrated HCl, stirred and then sodium nitrate (1.28) was added dropwise. g, 18.6 mmol) in 6 ml water at 0 ° C and the mixture was stirred at 0 ° C for 60 minutes. Then potassium acetate (4.56 g, 46.5 mmol) and acetylacetone (2.07 mL, 20.15 mmol) were added dropwise. The mixture was stirred at room temperature overnight, filtered. The solid was dissolved in CH 2 Cl 2, washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product (4.00 g, 67% yield) which was used directly in the next step: ¹H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 3H), 2.62 (s, 3H), 6.79-6.83 (m, 1H), 7.09-7.15 ( m, 1H), 7.43-7.47 (m, 1H), 14.57 (s, 1H).

219

Reference example 200

3 - [(2,6-Difluorophenyl) hydrazone] pentane-2,4-dione [0876] ο ο

F

<img file="PL2393360T3_D0204.tif" />

[0877] 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 hydrochloride solution, sodium nitrate (600 mg) was added dropwise.

9.3 mmol) in 2.7 ml of water at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. Then sodium acetate (1.78 g, 21.7 mmol) and acetylacetone (1 g, 10 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give the title compound (400 mg, 21% yield):¹H NMR (400 MHz, CDCl3): δ 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).

Reference example 201

3- (1H-Pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0878] [0879] Solution of 3- [3- (dimethylamino) prop-2-enoyl ] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (2.70 g, 8 mmol) and ΝΗ₂ΝΗ₂· Η₂Ο (1.94 mL, 40 mmol) in MeOH (25 mL) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: m.p. 192-194 ° C;¹H NMR (300 MHz,

<img file="PL2393360T3_D0205.tif" />

220 (1H, brs). LC-MS (ESI) m / z 307 [M + H]⁺. Anal. calc. for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.

Reference example 202

3 - [(4-Morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione [0880]

<img file="PL2393360T3_D0206.tif" />

[0881] 4-Morpholin-4-yaniline (653 mg, 3.67 mmol) was added to a mixture of 3 mL phosphoric acid (85%) and 2 mL nitric acid (65%) at -6 ° C. When the obtained mixture reached room temperature, it was cooled to -6 ° C and sodium nitrate (253 mg, 3.67 mmol) was added over 10 minutes. A small piece of ice (50 g) was added to the solution. The mixture was added at 0 ° C to a suspension of 2.4-pentanedione (367 mg, 3.67 mmol) and potassium acetate (20 g) in ethanol (250 ml). The solution was stirred for 15 minutes and then added to 250 mL saturated aqueous Na2CO3 solution, extracted with dichloromethane, washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (870 mg, 82% yield) as brown solid: ¹H NMR (400 MHz, CDCl3): δ 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).

Reference example 203

3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-morpholin-4-ylphenyl) pyridazin-4 (1H) -one [0882]

<img file="PL2393360T3_D0207.tif" />

[0883] 3 - [(4-Morpholin-4-yl-phenyl) hydrazone] pentane-2,4-dione (500 mg, 1.73 mmol) was dissolved in 10 ml of N, N-dimethylformamide dimethyl acetal. The mixture was heated to reflux for 4 hours and concentrated

221 under reduced pressure to obtain the title compound as a brown oil that was used in the next step without further purification: ¹H NMR (400 MHz, CDCl3): δ 2.85-2.90 (3H, m), 3.10-3.14 (3H, m), 3.18-3.21 (4H, m), 3 , 85-3.88 (4H, m), 5.63-5.66 (1H, m), 6.68 (1H, d, J = 8.0 Hz), 6.94-6.96 (2H , m), 7.45-7.48 (2H, m), 7.72 (1H, brs), 8.12 (1H, d, J = 8.0 Hz).

Reference example 204

3-Acetyl-1- (2-fluoro-5-iodophenyl) -5-methoxypyridazin-4 (1H) -one [0884]

<img file="PL2393360T3_D0208.tif" />

[0885] To a mixture of 1- (2-fluoro-5-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (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 N2. The mixture was stirred at -78 ° C for 2 hours. The reaction was quenched with saturated aqueous NH4Cl solution at -78 ° C. The mixture was diluted with saturated aqueous NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100 (0 to 0/100) and triturated with EtOAc / hexane to give the title compound (3.58 g, 92% yield) as a pale yellow solid: ¹H NMR (DMSO-d6, 300MHz): δ 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 Hz), 8.52 (1H, d, J = 1.5 Hz).

Reference example 205

1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0886]

222

<img file="PL2393360T3_D0209.tif" />

[0887] Suspension of 1- (2-fluoro-4-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.73 g, 4 mmol), pyrazole (0.408 g, 6 mmol), Cu2O (0.057 g, 0.4 mmol), salicylaldoxime (0.219 g, 1.6 mmol) and Cs2CO3 (2.60 g, 8 mmol) in CH3CN (8 mL) was refluxed at reflux for 6 hours in the atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH / H2O to give the title compound (0.370 g, 25% yield) as a white solid: m.p. 187-189C;¹H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.72 (3H, s), 3.93 (3H, s), 6.55 (1H, dd, J = 1, 5, 2.3 Hz), 7.60 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.71-7.77 (3H, m), 7.84 (1H , d, J =

2.3 Hz), 7.98 (1H, d, J = 2.6 Hz). Anal. calc. for C17H16FN5O4: C, 54.69; H, 4.32; N, 18.76. Found: C, 54.58; H, 4.40; N, 18.67.

Reference example 206

3-Acetyl-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one [0888]

<img file="PL2393360T3_D0210.tif" />

[0889] MeMgBr (1 M solution in THF, 2.8 mL, 2.8 mmol) was added dropwise at -78 ° C to a solution of 1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl ] -N, 5-dimethoxyN-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (351 mg, 0.94 mmol) in THF (100 mL). After stirring for 1 hour, the reaction mixture was quenched with 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH / H2O to give the title compound (223 mg, 72% yield) as a pale yellow solid: m.p. 159-161 ° C;¹H NMR (300

223

MHz, CDCl3): δ 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 (1H, d, J = 2.6 Hz). Anal. calc. for C16H13FN4O3: C, 58.54; H, 3.99; N, 17.07. Found: C, 58.42; H, 4.01; N, 16.98.

Reference example 207

Methyl 4-methoxy-3-oxo-2- (pyridin-3-ylhydrazone) [0890]

<img file="PL2393360T3_D0211.tif" />

[0891] A solution of 3-aminopyridine (20 g, 210 mmol) in a 6 M aqueous HCl solution (200 mL, 1200 mmol) was cooled with an ice bath. To the solution, a solution of sodium nitrate (18 g, 260 mmol) in water (40 mL) was added dropwise. After stirring at 0 ° C for 5 minutes, the mixture was added to a mixture of sodium acetate (130 g, 1300 mmol) and methyl 4-methoxyacetoacetate (28 mL, 210 mmol) in EtOH (300 mL) and water (150 mL) at a temperature of 0 ° C and the mixture was stirred at 0 ° C for 1 hour. The mixture was diluted with water (150 mL), extracted with AcOEt (500 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO3 (300 mL x 3) and brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (52 g, 97% yield) as a brown oil:¹H NMR (300 MHz, CDCl3): δ ppm 3.50 (3H x 1/2, s), 3.51 (3H x 1/2, s), 3.89 (3H x 1/2, s), 3.93 (3H x 1/2, s), 4.67 (2H x 1/2, s), 4.70 (2H x 1/2, s), 7.35-7.43 (1H, m ), 7.67-7.74 (1H x 1/2, m), 7.84-7.91 (1H x 1/2, m), 8.41-8.49 (1H, m), 8 , 64-8.71 (1H, m), 12.90 (1H x 1/2, s), 14.76 (1H x 1/2, brs).

Reference example 208

Methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate [0892]

<img file="PL2393360T3_D0212.tif" />

[0893] A mixture of methyl 4-methoxy-3-oxo-2- (pyridin-3-ylhydrazone) butanoate (52 g, 210 mmol) in N, N-dimethylformamide dimethyl acetal (80 mL, 600 mmol) was heated under reflux. reflux for 30 minutes. A mixture of

224 allowed to cool to room temperature and left at room temperature overnight. The resulting crystals were collected by filtration and washed with AcOEt to give the title compound (35 g, 64% yield) as pale yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 3.98 (3H, s), 7.48-7.54 (1H, m), 7.96 (1H, s) , 8.04 (1H, ddd, J = 8.4, 2.6, 1.5 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz), 8.93 (1H , d, J = 2.6 Hz).

Reference example 209

5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrochloride [0894]

<img file="PL2393360T3_D0213.tif" />

[0895] A solution of methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.7 mmol) in 6M aqueous HCl (20 mL) was heated under reflux at reflux for 4 hours. The mixture was concentrated under reduced pressure to obtain the title compound (2.1 g, 95% yield) as off-white crystals:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H, s), 7.78 (1H, dd, J = 8.7, 4.5 Hz), 8.36-8.42 ( 1H, m), 8.79 (1H, dd, J = 4.5, 1.1 Hz), 9.02 (1H, s), 9.15 (1H, d, J = 2.6 Hz).

Reference example 210

N, 5-Dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide [0896]

<img file="PL2393360T3_D0214.tif" />

[0897] A mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (1.0 g, 3.5 mmol), N hydrochloride, Dimethylhydroxylamine hydrochloride (0.52 g , 5.3 mmol), TEA (1.5 mL, 11 mmol) and O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (1.2 g, 3.9 mmol) in DMF (15 mL) was stirred at room temperature overnight. The mixture was diluted with

225

AcOEt. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed on basic silica gel (0 / 100-20 / 80 MeOH / AcOEt) to give the title compound (0.81 g, 79% yield) as white crystals:¹H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.48 (1H, dd, J = 8, 3, 4.5 Hz), 7.97 (1H, s), 8.00-8.05 (1H, m), 8.67 (1H, dd, J = 4.5, 1.3 Hz), 8.91 (1H, d, J = 2.6 Hz).

Reference example 211

3-Acetyl-5-methoxy-1-pyridin-3-yl-pyridazin-4 (1H) -one [0898]

<img file="PL2393360T3_D0215.tif" />

[0899] For a solution of N, 5-dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide (0.40 g, 1.4 mmol) in THF (10 mL ) was added dropwise with 1 M MeMgBr in THF (3.0 mL, 3.0 mmol) at -78 ° C. After stirring at -78 ° C for 2 hours, the mixture was quenched with water (0.5 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 (25 mL) and brine. The aqueous layer was extracted with CHCl3 (25 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 62% yield) as yellow crystals:¹H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.97 (3H, s), 7.49-7.56 (1H, m), 7.95 (1H, s) , 8.01-8.08 (1H, m), 8.72 (1H, dd, J = 4.7, 1.3 Hz), 8.95 (1H, d, J = 2.6 Hz).

Reference example 212

Methyl 2 - [(4-Bromo-2,5-difluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate [0900]

<img file="PL2393360T3_D0216.tif" />

Br [0901] A solution of NaNO2 (7.9 g, 115 mmol) in H2O (20 mL) was added dropwise at 0 ° C to a mixture of 4-bromo-2,5-difluoroaniline (20 g, 96 mmol) and 6 M aqueous HCl solution (96 ml, 576 mmol). After mixing for 15 minutes, obtained

226 the aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (12.4 mL, 96 mmol) and NaOAc (34 g, 576 mmol) in MeOH (165 mL) pre-cooled at 0 ° C. The precipitate was collected by filtration, washed with water and dried at room temperature to give the title compound (37 g, 100% yield) as a red solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.34 (3H, s), 3.83 (3H, s), 4.68 (2H, s), 7.70 (1H, dd, J = 9.7, 7.0 Hz), 7.89 (1H, dd, J = 10.6, 6.1 Hz), 12.16 (1H, s).

Reference example 213

Methyl 1- (4-Bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0902]

Br [0903] A solution of methyl 2 - [(4-bromo-2,5-difluorophenyl) hydrazone] -4-methoxy-3-oxobutanoate (33 g, 90 mmol) in N, N-dimethylformamide dimethyl acetal (72 ml) was stirred at 110 ° C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. MeOH and silica gel were added to the residue. The mixture was evaporated and purified by silica gel column chromatography eluting with hexane / AcOEt (1/0 to 0/1) and then AcOEt / MeOH (4/1) to give the title compound (27.9 g, 83% yield) as brown gum: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.80 (3H, s), 3.83 (3H, s), 8.01 (1H, dd, J = 8.7, 6.8 Hz) , 8.15 (1H, dd, J = 9.8, 6.0 Hz), 8.55 (1H, d, J = 1.5 Hz). LC-MS (ESI) m / z 376 [M + H]⁺.

Reference example 214

1- (4-Bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid [0904]

br

227 [0905] A solution of methyl 1- (4-bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (25 g, 68 mmol) and 2 M aqueous NaOH ( 68 ml) in EtOH (68 ml) was stirred at room temperature overnight. The solvent was removed by evaporation and the resulting aqueous solution was acidified with 6 M aqueous HCl (12 mL). The precipitate was collected by filtration and azeotroped with toluene to give the title compound (25 g, 100% yield) as a brown solid: LC-MS (ESI) m / z 376 [M + H]⁺.

Reference example 215

1- (4-Bromo-2,5-difluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0906]

<img file="PL2393360T3_D0217.tif" />

Br [0907] A mixture of 1- (4-bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (25 g, 83 mmol), N hydrochloride, Dimethylhydroxylamine (8, 9 g, 91 mmol), HOBt (12 g, 91 mmol), triethylamine (24 mL, 174 mmol) and WSC (17 g, 91 mmol) in DMF (160 mL) was stirred at room temperature for 18 hours. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1/0 to 0/1) and then AcOEt / MeOH (10/1) to give the title compound (11 g, 31% yield) as a yellow solid : LC-MS (ESI) m / z 405 [M + H]⁺.

Reference example 216

3-Acetyl-1- (4-bromo-2,5-difluorophenyl) -5-methoxypyridazin-4 (1H) -one [0908]

<img file="PL2393360T3_D0218.tif" />

[0909] A solution of 1- (4-bromo-2,5-difluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (5.0 g, 12 mmol) in THF (100 ml) was added dropwise

228 to MeMgBr (1.0 M in THF, 50 mL, 50 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 1 hour. The reaction was quenched with 1 M aqueous HCl (70 mL) at -78 ° C. The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain the title compound (3.6 g, 80% yield) as a yellow solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (3H, s), 3.80 (3H, s), 8.03 (1H, dd, J = 8.9, 6.6 Hz) , 8.17 (1H, dd, J = 10.0, 6.2 Hz), 8.52 (1H, d, J = 1.5 Hz). LC-MS (ESI) m / z 360 [M + H]⁺.

Reference example 217

5,5-Dimethyl-1,3-oxazolidin-2-one [0910]

<img file="PL2393360T3_D0219.tif" />

[0911] A mixture of 1-amino-2-methylpropan-2-ol (1.03 g, 11.6 mmol) and CDI (1.87 g, 11.6 mmol) in THF (40 mL) was stirred at room temperature for 15 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (AcOEt / hexane = 25% -100%) to obtain the title compound (1.13 g, 85% yield) as a colorless solid:¹H NMR (300 MHz, CDCl3): δ ppm 1.48 (6H, s), 3.35 (2H, s), 5.86 (1H, brs).

Reference example 218

4-Oxa-6-azaspiro [2,4] heptan-5-one [0912]

<img file="PL2393360T3_D0220.tif" />

[0913] A solution of 1- (aminomethyl) cyclopropanol (0.58 g, 6.7 mmol) and CDI (1.1 g, 6.7 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (25 / 75-70 / 30 AcOEt / hexane) to obtain the title compound (0.42 g, 56% yield) as white crystals:¹H NMR (300 MHz, CDCl3): δ ppm 0.680.75 (2H, m), 1.20-1.27 (2H, m), 3.68 (2H, s), 5.48 (1H, brs) .

229

Reference example 219

1- (4-Iodo-2-methoxyphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0914]

<img file="PL2393360T3_D0221.tif" />

[0915] A solution of NaNO2 (24.8 g, 360 mmol) in H2O (75 mL) was added dropwise at 0 ° C to a mixture of 2-fluoro-4-iodoaniline (71.1 g, 300 mmol) and a 6 M aqueous solution HCl (300 ml). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (43.8 g, 300 mmol) and NaOAc (147.6 g, 1.8 mol) in MeOH (600 mL) pre-cooled at 0 ° C. The precipitate was collected by filtration, washed with water, air dried overnight. A solution of the product in N, N-dimethylformamide dimethyl acetal (450 mL) was heated under reflux for 4 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane / AcOEt (1/1). The obtained products (54 g) were used in the next reaction without further purification.

[0916] To a suspension of products (54 g) in THF / MeOH (1/1, 400 mL) was added 10% aqueous NaOH (200 mL) at 0 ° C. The mixture was stirred at room temperature for 45 minutes. A 10% aqueous HCl solution (200 ml) was added to the suspension at 0 ° C. The mixture was stirred at room temperature for 1 hour. The precipitates were collected by filtration and washed with^andPr2O. The obtained products (45 g) were used in the next reaction without further purification.

[0917] A mixture of products (45 g), N-methoxymethanamine hydrochloride (12.4 g, 127 mmol), HOBt (18.7 g, 138 mmol), WSC (26.5 g, 138 mmol) and Et3N (48, 2 mL, 346 mmol) in DMF (500 mL) was stirred at room temperature overnight. The mixture was partitioned between AcOEt and H2O and the organic layer was washed with an aqueous NaCl solution, dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (AcOEt / MeOH = 100/0 to 95/5) to give the title compound (32.7 g, 20% yield) as a white solid and 1- (2-fluoro-4 iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (10 g, 6% yield) as a white solid. ¹H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.70 (3H, s), 3.88 (3H, s), 3.89 (3H, s), 7.23

230 (1H, d, J = 8.3 Hz), 7.37 (1H, d, J = 1.9 Hz), 7.43 (1H, dd, J = 8.3, 1.9 Hz), 7 , 77 (1H, s). LC-MS (ESI) m / z 446 [M + H]⁺.

Reference example 220

N, 5-Dimethoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0918]

<img file="PL2393360T3_D0222.tif" />

[0919] Suspension of 1- (4-iodo-2-methoxyphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (10.7 g, 24 mmol), pyrazole (1 , 63 g, 24 mmol), Cu2O (0.343 g, 2.4 mmol), salicylaldoxime (1.32 g, 9.6 mmol) and Cs2CO3 (15.6 g, 48 mmol) in CH3CN (100 mL) heated under reflux condenser at reflux for 4 hours in an atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt / THF (1 / 0-0 / 1) to give the title compound (6.32 g, 68% yield) as a pale yellow amorphous solid:¹H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.73 (3H, s), 3.91 (3H, s), 3.99 (3H, s), 6.53 (1H, dd, J = 1.9, 2.3 Hz), 7.27 (1H, dd, J = 2.3, 8.7 Hz), 7.58 (1H, d, J = 8.7 Hz), 7.61 (1H, d, J = 1.9 Hz), 7.77 (1H, d, J = 1.5 Hz), 7.84 (1H, s), 7.98 (1H, d, J = 2.3 Hz).

Reference example 221

3-Acetyl-5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one [0920]

<img file="PL2393360T3_D0223.tif" />

[0921] MeMgBr (1 M solution in THF, 50 mL, 50 mmol) was added dropwise at -78 ° C to a solution of N, 5-dimethoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl ) phenyl] -N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (6.32 g, 16.4 mmol) in THF (100 mL). After

231 with stirring for 1 hour, the reaction mixture was quenched with 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH to give the title compound (1.53 g, 27% yield) as pale yellow bars: m.p. 193-196 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 6.54 (1H, dd, J = 1, 9, 2.3 Hz), 7.30 (1H, dd, J = 2.3, 8.7 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.63 (1H, d, J = 2.3 Hz), 7.777.78 (2H, m), 8.00 (1H, d, J = 2.3 Hz). Anal. calc. for C17H16N4O4: C, 59.99; H, 4.74; N, 16.46. Found: C, 59.68; H, 5.00; N, 16.26.

Reference example 222

4- (2,3-Difluoro-4-nitrophenyl) morpholine [0922]

<img file="PL2393360T3_D0224.tif" />

[0923] A mixture of 1,2,3-trifluoro-4-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol) and K2CO3 (4.8 g, 35 mmol) in DMSO (35 ml) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (11.5 g, 67% yield) as a pale yellow solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.09-3.51 (4H, m), 3.58-4.08 (4H, m), 6.98 (1H, ddd, J = 9 , 8, 8.1, 2.1 Hz), 7.94 (1H, ddd, J = 9.9, 8.0, 2.1 Hz). LC-MS (ESI) m / z 245 [M + H]⁺.

Reference example 223

2,3-Difluoro-4-morpholin-4-ylaniline [0924]

<img file="PL2393360T3_D0225.tif" />

[0925] A mixture of 4- (2,3-difluoro-4-nitrophenyl) morpholine (11.5 g, 47 mmol) and 10% Pd-C (50% wet, 1.2 g) in EtOH (150 ml) was hydrogenated for 5 hours at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated under

232 reduced pressure. The residue was recrystallized from^andPr2O / AcOEt to obtain the title compound (8.7 g, 86% yield) as a bright red powder: ¹H NMR (300 MHz, DMSO-d6): δ ppm 2.77-2.95 (4H, m), 3.60-3.79 (4H, m), 5.07 (2H, s), 6, 49 (1H, td, J = 9.0, 1.9 Hz), 6.62 (1H, td, J = 8.9, 2.3 Hz). LC-MS (ESI) m / z 215 [M + H]⁺.

Reference example 224

Methyl 2 - [(2,3-Difluoro-4-morpholin-4-ylphenyl) hydrazone] -4-methoxy-3-oxobutanoate [0926]

<img file="PL2393360T3_D0226.tif" />

[0927] A solution of NaNO2 (3.4 g, 49 mmol) in H2O (10 mL) was added dropwise at 0 ° C to a mixture of 2,3-difluoro-4-morpholin-4-ylaniline (8.7 g, 41 mmol ) and 6 M aqueous HCl (41 mL, 244 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (5.2 mL, 41 mmol) and NaOAc (14.3 g, 244 mmol) in MeOH (40 mL) pre-cooled at 0 ° C. The mixture was adjusted to pH 7 with 1 M aqueous NaOH (200 mL). The precipitate was collected by filtration, washed with water and dried at room temperature to give the title compound (4.7 g, 31% yield) as a red solid: LC-MS (ESI) m / z 372 [M + H]⁺.

Reference example 225

Methyl 1- (2,3-Difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0928]

<img file="PL2393360T3_D0227.tif" />

[0929] A solution of methyl 2 - [(2,3-difluoro-4-morpholin-4-ylphenyl) hydrazono] -4-methoxy-3-oxobutanoate (4.7 g, 13 mmol) in N, N-dimethylformamide dimethyl acetal

233 (20 ml) was stirred at 100 ° C for 80 minutes. After cooling to room temperature, the precipitate was collected by filtration and washed with^andPr2O to obtain the title compound (4.1 g, 84% yield) as a brown powder: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.13 (4H, dt, J = 4.4, 2.5 Hz), 3.49-4.05 (10H, m), 7.03 ( 1H, td, J = 8.8, 2.5 Hz), 7.51 (1H, td, J = 8.5, 2.3 Hz), 8.53 (1H, d, J = 1.5 Hz ). LC-MS (ESI) m / z 382 [M + H]⁺.

Reference example 226

Acid, 1- (2,3-Difluoro-4-morpholin-4-yl-phenyl) -5-methoxy-4-oxo-1,4-dihydro-pyridazine-3-carboxylic acid [0930]

<img file="PL2393360T3_D0228.tif" />

[0931] A solution of methyl 1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 11 mmol) and 2 M aqueous NaOH (11 mL, 22 mmol) in EtOH (20 mL) was stirred at room temperature for 16 hours. A 1 M aqueous HCl solution (21 ml) was added to the mixture. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (3.8 g, 98% yield) as a white solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.06-3.23 (4H, m), 3.66-3.82 (4H, m), 3.88 (3H, s), 6, 84-7.27 (1H, m), 7.36-7.74 (1H, m), 8.86 (1H, d, J = 1.1 Hz), 14.95 (1H, brs). LC-MS (ESI) m / z 368 [M + H]⁺.

Reference example 227

1- (2,3-Difluoro-4-morpholin-4-ylphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0932]

<img file="PL2393360T3_D0229.tif" />

[0933] A mixture of 1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 10 mmol), N hydrochloride , O234 dimethylhydroxylamine (1.1 g, 11 mmol), HOBt (1.5 g, 11 mmol), triethylamine (2.9 mL, 21 mmol) and WSC (2.2 g, 11 mmol) in DMF (20 mL ) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure to give the title compound (3.3 g, 77% yield) as a brown solid: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.05-3.18 (4H, m), 3.24 (3H, s), 3.57 (3H, s), 3.684.02 (7H, m), 7.03 (1H, td, J = 8.8, 2.1 Hz), 7.27-7.81 (1H, m), 8.50 (1H, s). LC-MS (ESI) m / z 411 [M + H]⁺.

Reference example 228

3-Acetyl-1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxypyridazin-4 (1H) -one [0934]

<img file="PL2393360T3_D0230.tif" />

[0935] Solution of 1- (2,3-difluoro-4-morpholin-4-ylphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.1 g, 2 , 6 mmol) in THF (25 mL) was added dropwise to MeMgBr (1.0 M in THF, 11 mL, 11 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 1 hour. The reaction was quenched with 1 M aqueous HCl (11 mL) at -78 ° C. The mixture was warmed to room temperature, diluted with AcOEt and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from^andPr2O / AcOEt to obtain the title compound (870 mg, 92% yield) as a pale yellow solid: ¹H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.90-3.28 (4H, m), 3.64-4.01 (7H, m), 7, 05 (1H, td, J = 8,9,2,3 Hz), 7,53 (1H, td, J = 8,6, 2,5 Hz), 8.50 (1H, d, J = 1, 9 Hz). LC-MS (ESI) m / z 366 [M + H]⁺.

Reference example 229

4- (2,5-Difluoro-4-nitrophenyl) morpholine [0936]

235

<img file="PL2393360T3_D0231.tif" />

[0937] A mixture of 1,2,4-trifluoro-5-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol) and K2CO3 (4.8 g, 35 mmol) in DMSO (35 ml) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (10 g, 63% yield) as a pale yellow solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.15-3.49 (4H, m), 3.50-3.90 (4H, m), 7.13 (1H, dd, J = 14 , 3, 7.5 Hz), 8.01 (1H, dd, J = 13.6, 7.5 Hz). LC-MS (ESI) m / z 245 [M + H]⁺.

Reference example 230

2,5-Difluoro-4-morpholin-4-ylaniline [0938]

<img file="PL2393360T3_D0232.tif" />

[0939] A mixture of 4- (2,5-difluoro-4-nitrophenyl) morpholine (11 g, 44 mmol) and 10% Pd-C (50% wet, 1.1 g) in EtOH (150 ml) was hydrogenated for 5 hours at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from^andPr2O / AcOEt to obtain the title compound (8.6 g, 91% yield) as a bright red powder: ¹H NMR (300 MHz, DMSO-d6): δ ppm 2.66-2.95 (4H, m), 3.56-3.83 (4H, m), 5.00 (2H, s), 6, 55 (1H, dd, J = 13.8, 8.5 Hz), 6.77 (1H, dd, J = 12.8, 8.3 Hz). LC-MS (ESI) m / z 215 [M + H]⁺.

Reference example 231

Methyl 2 - [(2,5-Difluoro-4-morpholin-4-ylphenyl) hydrazone] -4-methoxy-3-oxobutanoate [0940]

236

<img file="PL2393360T3_D0233.tif" />

[0941] A solution of NaNO2 (3.3 g, 48 mmol) in H2O (10 mL) was added dropwise at 0 ° C to a mixture of 2,5-difluoro-4-morpholin-4-ylaniline (8.6 g, 40 mmol ) and 6 M aqueous HCl (40 mL, 240 mmol). After stirring for 15 minutes, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (5.2 mL, 40 mmol) and NaOAc (14 g, 240 mmol) in MeOH (40 mL) pre-cooled at 0 ° C. The mixture was adjusted to pH 7 with 1 M aqueous NaOH (200 mL). The precipitate was collected by filtration, washed with water and dried at room temperature to give the title compound (9.51 g, 64% yield) as a red solid: LC-MS (ESI) m / z 372 [M + H]⁺.

Reference example 232

Methyl 1- (2,5-Difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate [0942]

<img file="PL2393360T3_D0234.tif" />

[0943] A solution of methyl 2 - [(2,5-difluoro-4-morpholin-4-ylphenyl) hydrazono] -4-methoxy-3oxobutanoate (2.8 g, 7.5 mmol) in N, N-dimethylformamide dimethyl acetal (18 ml) was stirred at 100 ° C for 80 minutes. After cooling to room temperature, the precipitate was collected by filtration and washed with^andPr2O to obtain the title compound (2.7 g, 95% yield) as a brown powder: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.12 (4H, dt, J = 4.4, 2.5 Hz), 3.48-4.31 (10H, m), 7.18 ( 1H, dd, J = 12.5, 7.6 Hz), 7.72 (1H, dd, J = 12.5, 7.2 Hz), 8.50 (1H, s). LC-MS (ESI) m / z 382 [M + H]⁺.

Reference example 233

1- (2,5-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

237 [0944]

<img file="PL2393360T3_D0235.tif" />

[0945] A solution of methyl 1- (2,5-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (2.7 g, 7.1 mmol) and A 2 M aqueous solution of NaOH (7.2 mL, 14.4 mmol) in EtOH (14 mL) was stirred at room temperature for 16 hours. A 1 M aqueous HCl solution (14 ml) was added to the mixture. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (2.5 g, 96% yield) as a white solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 3.00-3.24 (4H, m), 3.67-3.82 (4H, m), 3.88 (3H, s), 7, 23 (1H, dd, J = 12.7, 7.7 Hz), 7.74 (1H, dd, J = 12.8, 7.2 Hz), 8.83 (1H, d, J = 1, 1 Hz), 14.95 (1H, brs). LC-MS (ESI) m / z 368 [M + H]⁺.

Reference example 234

1- (2,5-Difluoro-4-morpholin-4-ylphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide [0946]

<img file="PL2393360T3_D0236.tif" />

[0947] A mixture of 1- (2,5-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (2.5 g, 6.8 mmol), N, Odimethylhydroxylamine hydrochloride (0.73 g, 7.5 mmol), HOBt (1.0 g, 7.5 mmol), triethylamine (2.0 mL, 14 mmol) and WSC (1.4 g, 7.5 mmol) in DMF (28 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure to give the title compound (1.6 g, 58% yield) as a brown solid: ¹H NMR (300 MHz, DMSO-d6): δ ppm 3.01-3.19 (4H, m), 3.24 (3H, s), 3.56 (3H, s), 3.623,91 (7H, m), 7.17 (1H, dd, J = 12.7, 7.7 Hz), 7.62-7.82 (1H, m), 8.48 (1H, s). LC-MS (ESI) m / z 411 [M + H]⁺.

238

Reference example 235

3-Acetyl-1- (2,5-difluoro-4-morpholin-4-ylphenyl) -5-methoxypyridazin-4 (1H) -one [0948]

<img file="PL2393360T3_D0237.tif" />

[0949] Solution of 1- (2,5-difluoro-4-morpholin-4-ylphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (0.51 g, 1 , 2 mmol) in THF (40 mL) was added dropwise to MeMgBr (1.0 M in THF, 5.0 mL, 5.0 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 2 hours. The reaction was quenched with 1 M aqueous HCl (5.0 mL) at -78 ° C. The mixture was warmed to room temperature, diluted with AcOEt and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt / MeOH (10/0 to 10/1) to give the title compound (340 mg, 75% yield) as a pale yellow solid:¹H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.91-3.21 (4H, m), 3.54-3.89 (7H, m), 7, 19 (1H, dd, J = 12.7, 7.7 Hz), 7.74 (1H, dd, J = 12.8, 7.2 Hz), 8.46 (1H, d, J = 1, 5 Hz). LCMS (ESI) m / z 366 [M + H]⁺.

Example 1 (Comparative)

3- [1- (4-Methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0950]

<img file="PL2393360T3_D0238.tif" />

[0951] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (337 mg, 1.0 mmol) in ethanol (100 ml) 4-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC provided

239

3- [1- (4-methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a pale yellow solid (108 mg, 27%).

[0952] ¹H NMR (400 MHz, DMSO-d6): δ ppm 2.33 (s, 3H), 6.68 (d, J = 8 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H ), 7.29-7.23 (m, 4H), 7.46 (d, J = 8 Hz, 1H), 7.50 (s, 1H), 7.62 (t, J = 8 Hz, 1H ), 7.72 (d, J = 8 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 397.15; temp.top. 164-165 ° C.

Example 2 (Comparative)

3- [1- (4-Fluorophenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0953]

<img file="PL2393360T3_D0239.tif" />

[0954] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (337 mg, 1.0 mmol) in ethanol (100 ml) 4-fluorophenylhydrazine hydrochloride (244 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (4-fluorophenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light brown solid (119 mg, thirty%).

[0955] ¹H NMR (400 MHz, DMSO-d6): δ ppm 6.68 (d, J = 8 Hz, 1H), 7.29-7.24 (m, 3H), 7.50-7.45 (m, 3H), 7.62 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 1H), 7.84 (d , J = 1.6 Hz, 1H), 8.95 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 401.14; temp.top. 130 131 ° C.

Example 3 (Comparative)

3- [1- (4-Chloro-phenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one [0956]

<img file="PL2393360T3_D0240.tif" />

240 To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) 4-chlorophenylhydrazine hydrochloride (269 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (4-chlorophenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light brown solid (126 mg, 30% ).

[0958] ¹H NMR (400 MHz, DMSO-d6): δ ppm 6.69 (d, J = 8 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 7.51-7.47 (m, 4H), 7.57 (m, 2H), 7.68 (t, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 8.98 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 417.08; temp.top. 166-167 ° C.

Example 4 (Comparative)

3- [1- (4-Methoxyphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0959]

<img file="PL2393360T3_D0241.tif" />

[0960] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) 4-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (4-methoxyphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light yellow solid (154 mg, 37% ).

[0961] ¹H NMR (400 MHz, DMSO-d6): δ ppm 3.76 (s, 3H), 6.67 (d, J = 8 Hz, 1H), 6.98 (d, J = 8 Hz, 2H), 7.20 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 1H), 7.55 (s, 1H), 7.62 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 413.16; temp.top. 173-174 ° C.

Example 5 (Comparative)

3- [1- (3-Methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0962]

241

<img file="PL2393360T3_D0242.tif" />

[0963] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) 3-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (3-methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light yellow solid (84 mg, 21% ).

[0964] ¹H NMR (400 MHz, DMSO-d6): δ ppm 2.31 (s, 3H), 6.68 (d, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.32-7.28 (m, 2H), 7.43 (d, J = 8 Hz, 1H), 7.49 (s, 1H), 7.62 (t, J = 8 Hz, 1H), 7.72 (d, J = 8 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 8.94 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 397.18; temp.top. 142-143 ° C.

Example 6 (Comparative)

3- [1- (3-Fluorophenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0965]

<img file="PL2393360T3_D0243.tif" />

[0966] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (674 mg, 2.0 mmol) in ethanol ( 200 ml) 3-fluorophenylhydrazine hydrochloride (488 mg, 3.0 mmol) and Et3N (0.56 ml, 4.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (3-fluoro-phenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) -phenyl] -pyridazin-4 (1H) -one as a light yellow solid (201 mg, 25% ).

[0967] ¹H NMR (400 MHz, DMSO-d6): δ ppm 6.69 (d, J = 8 Hz, 1H), 7.24-7.20 (m, 2H), 7.26 (d, J = 2, 0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.46 (q, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.61 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.74 (d, J = 8Hz, 1H), 7.87 (d, J = 2.0 Hz , 1H), 8.97 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 401.14; temp.top. 104-105 ° C.

242

Example 7 (Comparative)

3- [1- (2-Methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [0968]

<img file="PL2393360T3_D0244.tif" />

[0969] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) 2-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (2-methylphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light pink solid (85 mg, 21% ).

[0970] ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.92 (s, 3H), 6.68 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.31-7.28 (m, 1H), 7.38-7.35 (m, 2H), 7.42 (d, J = 2, 0 Hz, 1H), 7.56 (t, J = 8 Hz, 2H), 7.70 (d, J = 8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 397.11; temp.top. 126-127 ° C.

Example 8 (Comparative)

3-1- (2-Chloro-phenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] -pyridazin-4 (1H) on [0971]

<img file="PL2393360T3_D0245.tif" />

To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (674 mg, 2.0 mmol) in ethanol ( 200 ml) 2-chlorophenylhydrazine hydrochloride (538 mg, 3.0 mmol) and Et3N (0.56 ml, 4.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (2-chlorophenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light yellow solid (280 mg, 34%) ).

243 [0973] ¹H NMR (400 MHz, DMSO-d6): δ ppm 6.70 (d, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz, 1H), 7.61-7.48 (m , 7H), 7.71 (d, J = 8 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 8.90 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 417.08; temp.top. 139-140 ° C.

Example 9 (Comparative)

3- [1- (2-Methoxyphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazine 4 (1H) -one [0974]

<img file="PL2393360T3_D0246.tif" />

[0975] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) 2-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 ml, 2.0 mmol) were added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative HPLC gave 3- [1- (2-methoxyphenyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light yellow solid (78 mg, 19% ).

[0976] ¹H NMR (400 MHz, DMSO-d6): δ ppm 3.46 (s, 3H), 6.69 (d, J = 8 Hz, 1H), 7.03 (d, J = 8 Hz, 1H), 7 , 14 (t, J = 8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.41 (t, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.68 (d, J = 8Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 8.90 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 413.16; temp.top. 146-147 ° C.

Example 10 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0977]

<img file="PL2393360T3_D0247.tif" />

To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (337 mg, 1.0 mmol) in ethanol ( 100 ml) phenylhydrazine (163 mg, 1.5 mmol) was added. The mixture was stirred at 100 ° C for 3 hours and the solvent removed under reduced pressure. Preparative chromatography

244

HPLC provided 3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one as a gray solid (55 mg, 15%).

[0979] ¹H NMR (400 MHz, DMSO-d6): δ ppm 6.68 (d, J = 8 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.48-7.39 (m, 6H), 7.51 (s, 1H), 7.61 (t, J = 8 Hz, 1H), 7.71 (d, J = 8Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 8 Hz, 1H). LC-MS (MH⁺) 383.15; temp.top. 156-157 ° C.

Example 11 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1- [4- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [0980]

<img file="PL2393360T3_D0248.tif" />

cf₃ [0981] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [4- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (crude, 718 mg, 2.13 mmol) in 20 ml of methanol were added phenylhydrazine (345 mg, 3.20 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3- (1-phenyl-1H-pyrazol-5-yl) -1- [4- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 12% for two stages) as a yellow solid.

[0982] ¹H NMR (300 MHz, CDCl3): δ ppm 6.74 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 7.39-7.41 (m, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.44-7.50 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H) , 7.81 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 minutes) purity is&gt; 95%, Rt = 3.422 min; MS calculated: 382, ​​MS Found: 383 (M⁺+ H); temp.top. 237-238 ° C.

Example 12 (Comparative)

1- (3-Chloro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [0983]

245

<img file="PL2393360T3_D0249.tif" />

[0984] To a solution of 1- (3-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin 4 (1H) -one (crude, 573 mg, 1.89 mmol) in 20 ml of methanol was added phenylhydrazine (306 mg, 2.84 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (3-chlorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (125 mg, 19% for two steps) in the form of a yellow solid.

[0985] ¹H NMR (300 MHz, DMSO-d6): δ ppm 6.71-6.74 (m, 2H), 6.80-6.83 (m, 1H), 7.22-7.25 (m, 2H ), 7.39-7.49 (m, 6H), 7.81 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.150 min; MS Calc .: 348, MS Found: 349 (M⁺+ H); temp.top. 146-147 ° C.

Example 13 (Comparative)

1- (2-Methoxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [0986]

<img file="PL2393360T3_D0250.tif" />

[0987] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-methoxyphenyl) pyridazin 4 (1H) -one (crude, 639 mg, 2.14 mmol) in 20 ml methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (2-methoxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (35 mg, 5% for two steps) in the form of a yellow solid.

[0988] ¹H NMR (400 MHz, CDCl3): δ ppm 3.82 (s, 3H), 6.37 (dd, J = 10.4, 2.4 Hz, 1H), 6.60 (d, J = 10, 0 Hz, 1H), 6.78-6.83 (m, 1H), 6.96 (dd, J = 11.2, 1.6 Hz, 1H), 7.25 (d, J =

246

<img file="PL2393360T3_D0251.tif" />

(mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.589 min; MS Calc .: 344, MS Found: 345 (M⁺+ H); temp.top. 153-154 ° C.

Example 14 (Comparative)

1- (4-Methoxy-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [0989] [0990] For a solution of 3- [3- (dimethylamino) prop-2 -enoyl] -1- (4-methoxyphenyl) pyridazine (1H) -one (crude, 640 mg, 2.14 mmol) in 20 mL methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (4-methoxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (127 mg, 17% for two steps) in the form of a yellow solid.

[0991] ¹H NMR (400 MHz, CDCl3): δ ppm 3.81 (s, 3H), 6.67-6.76 (m, 5H), 7.38-7.44 (m, 6H), 7.78 ( d, J = 2.8 Hz, 1H), 8.08 (d, J = 10.4 Hz, 1H); LCMS (mobile phase: from

70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min.) Purity is&gt; 95%, Rt = 2.639 min; MS Calc .: 344, MS Found: 345 (M⁺+ H); temp.top. 179-180 ° C.

Example 15 (Comparative)

1- (3-Fluoro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [0992] [0993] For 3- [3- (dimethylamino) prop-2 solution -enoyl] -1- (3-fluorophenyl) pyridazine-4 (1H) -one (crude, 840 mg, 2.93 mmol) in 20 ml of methanol added phenylhydrazine (474

247 mg, 4.39 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (3-fluorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (169 mg, 17% for two steps) in the form of a yellow solid.

[0994] ¹H NMR (400 MHz, CDCl3): δ ppm 6.36-6.41 (m, 1H), 6.68-6.75 (m, 2H), 6.957.01 (m, 1H), 7.24- 7.32 (m, 1H), 7.38-7.49 (m, 6H), 7.79 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 10.4 Hz , 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.834 min; MS Calc .: 332, MS Found: 333 (M⁺+ H); temp.top. 170-171 ° C.

Example 16 (Comparative)

1- (2-Fluoro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [0995]

<img file="PL2393360T3_D0252.tif" />

[0996] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-fluorophenyl) pyridazin 4 (1H) -one (crude, 776 mg, 2.70 mmol) in 20 ml methanol was added phenylhydrazine (438 mg, 4.10 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (2-fluorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (278 mg, 31% for two steps) in the form of a yellow solid.

[0997] ¹H NMR (300 MHz, CDCl3): δ ppm 6.39-6.46 (m, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.97-7.03 (m, 1H), 7.13-7.20 (m, 1H), 7.27-7.46 (m, 7H), 7.78 (d, J = 1.8 Hz, 1H), 8.02 (dd , J = 7.8, 2.4 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.634 min; MS Calc .: 332, MS Found: 333 (M⁺+ H); temp.top. 124 125 ° C.

248

Example 17 (Comparative)

1- (4-Fluoro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [0998]

<img file="PL2393360T3_D0253.tif" />

[0999] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-fluorophenyl) pyridazin 4 (1H) -one (crude, 840 mg, 2.93 mmol) in 20 ml methanol was added phenylhydrazine (474 mg, 4.39 mmol) The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (4-fluorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (260 mg, 27% for two steps) as a brown solid.

[1000] ¹H NMR (300 MHz, DMSO-d6): δ ppm 6.62 (d, J = 7.8 Hz, 1H), 7.11-7.15 (m, 2H), 7.20-7.26 ( m, 3H), 7.37-7.40 (m, 2H), 7.44-7.49 (m, 3H), 7.81 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 8.1 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.779 min; MS Calc .: 332, MS Found: 333 (M⁺+ H); temp.top. 252 253 ° C.

Example 18 (Comparative)

1- (4-Chloro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [1001]

<img file="PL2393360T3_D0254.tif" />

Cl [1002] To a solution of 1- (4-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin 4 (1H) -one (crude, 764 mg, 2.52 mmol) in 20 ml methanol was added phenylhydrazine (408 mg, 3.78 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC

249 to obtain 1- (4-chlorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (70 mg, 8% for two steps) as a brown solid.

[1003] ¹H NMR (300 MHz, CDCl3): δ ppm 6.68-6.73 (m, 3H), 7.24 (dd, J = 6.9, 2.4 Hz, 2H), 7.38-7, 46 (m, 6H), 7.78 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.180 min; MS Calc .: 348, MS Found: 349 (M⁺+ H); temp.top. 219-220 ° C.

Example 19 (Comparative)

1- (2-Methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1004]

<img file="PL2393360T3_D0255.tif" />

[1005] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-methylphenyl) pyridazin 4 (1H) -one (crude, 1298 mg, 4.59 mmol) in 20 ml methanol was added phenylhydrazine (744 mg, 6.89 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (2-methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (180 mg, 12% for two steps) in the form of a yellow solid.

[1006] ¹H NMR (400 MHz, CDCl3): δ ppm 2.01 (s, 3H), 6.67 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H ), 7.15-7.25 (m, 2H), 7.29-7.38 (m, 7H), 7.79-7.83 (m, 2H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.679 min; MS Calc .: 328, MS Found: 329 (M⁺+ H); temp.top. 120-121 ° C.

Example 20 (Comparative)

1- (3-Methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1007]

<img file="PL2393360T3_D0256.tif" />

250 [1008] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-methylphenyl) pyridazin 4 (1H) -one (crude, 650 mg, 2.29 mmol) in 20 ml methanol was added phenylhydrazine (370 mg, 3.44 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (3-methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (55 mg, 7% for two steps) as a brown solid.

[1009] ¹H NMR (400 MHz, CDCl3): δ ppm 2.32 (s, 3H), 6.60 (s, 1H), 6.72-6.74 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.41-7.50 (m, 6H), 7.81 (s, 1H), 8.19 ( d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.972 min; MS Calc .: 328, MS Found: 329 (M⁺+ H); temp.top. 115-116 ° C.

Example 21 (Comparative)

1- (3-Methoxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1010]

<img file="PL2393360T3_D0257.tif" />

[1011] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (3-methoxyphenyl) pyridazin 4 (1H) -one (crude, 640 mg, 2.14 mmol) in 20 ml methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (3-methoxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (106 mg, 14% for two steps) in the form of a yellow solid.

[1012] ¹H NMR (400 MHz, CDCl3): δ ppm 3.76 (s, 3H), 6.46 (dd, J = 8.0, 1.6 Hz, 1H), 6.51 (t, J = 2, 0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.35-7.43 (m, 6H), 7.81 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.753 min; MS Calc .: 344, MS Found: 345 (M⁺+ H); temp.top. 110-111 ° C.

251

Example 22 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1- [2- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1013]

<img file="PL2393360T3_D0258.tif" />

[1014] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [2- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (crude, 785 mg, 2.33 mmol) in 20 ml of methanol were added phenylhydrazine (377 mg, 3.50 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3- (1-phenyl-1H-pyrazol-5-yl) -1- [2- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (105 mg, 12% for two stages) as a yellow solid.

[1015] ¹H NMR (400 MHz, CDCl3): δ ppm 6.59 (d, J = 7.6 Hz, 1H), 6.97-7.00 (m, 1H), 7.14 (d, J = 2, 0 Hz, 1H), 7.27-7.35 (m, 5H), 7.57-7.60 (m, 2H), 7.75-7.81 (m, 3H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.896 min; MS Calc .: 382, ​​MS Found: 383 (M⁺+ H); temp.top. 145-146 ° C.

Example 23 (Comparative)

1- (4-Morpholin-4-ylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1016]

<img file="PL2393360T3_D0259.tif" />

[1017] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-morpholin-4-phenyl) pyridazin-4 (1H) -one (crude, 1100 mg, 3.11 mmol) in 20 ml methanol added phenylhydrazine (504 mg, 4.67 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. Residue

252 purified by prep-HPLC to give 1- (4-morpholin-4-yl-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one (95 mg, 8% for two steps ) in the form of a yellow solid.

[1018] ¹H NMR (400 MHz, CDCl3): δ ppm 3.19 (t, J = 4.8 Hz, 4H), 3.89 (t, J = 4.8 Hz, 4H), 6.71-6.79 (m, 5H), 7.40-7.48 (m, 6H), 7.82 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.391 min; MS Calc .: 399, MS Found: 400 (M⁺+ H); temp.top. 205-206 ° C.

Example 24 (Comparative)

1-Phenyl-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1019]

<img file="PL2393360T3_D0260.tif" />

[1020] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1-phenylpyridazin-4 (1H) -one (crude, 620 mg, 2.30 mmol) in 20 ml methanol was added phenylhydrazine (996 mg , 9.22 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-phenyl-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (50 mg, 7% yield for two steps) as a yellow solid body.

[1021] ¹H NMR (400 MHz, CDCl3): δ ppm 6.71 (d, J = 8.0 Hz, 1H), 6.81-6.84 (m, 2H), 7.29-7.30 (m, 3H), 7.40-7.47 (m, 6H), 7.79 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.548 min; MS Calc .: 314, MS Found: 315 (M⁺+ H); temp.top. 179-180 ° C.

Example 25 (Comparative)

1- (4-Methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1022]

253

<img file="PL2393360T3_D0261.tif" />

[1023] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-methylphenyl) pyridazin 4 (1H) -one (crude, 600 mg, 2.12 mmol) in 20 ml methanol was added phenylhydrazine (916 mg, 8.48 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (4-methylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (50 mg, 7% for two steps) in the form of a yellow solid.

[1024] ¹H NMR (400 MHz, CDCl3): δ ppm 2.34 (s, 3H), 6.69 (d, J = 7.6 Hz, 3H), 7.08 (d, J = 8.4 Hz, 2H ), 7.40-7.47 (m, 6H), 7.79 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H);

LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.789 min; MS Calc .: 328, MS Found: 329 (M⁺+ H); temp.top. 182-183 ° C.

Example 26 (Comparative)

1- [2- (Difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1025] [1026] For 1- [2- (difluoromethoxy) solution phenyl] -3- [3- (dimethylamino) prop-2-yloyl] pyridazin-4 (1H) -one (crude, 622 mg, 1.85 mmol) in 20 ml of methanol, phenylhydrazine (800 mg, 7.40 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- [2- (difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (30 mg, 4% for two steps ) in the form of a yellow solid.

254 [1027] ¹H NMR (400 MHz, CDCl3): δ ppm 6.38 (t, J = 72.0 Hz, 1H), 6.57-6.60 (m, 1H), 6.63 (d, J = 8, 0 Hz, 1H), 7.13 (dd, J = 8.0, 0.8 Hz, 1H), 7.23-7.26 (m, 2H), 7.36-7.40 (m, 6H ), 7.78 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 80% water and 20% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.317 min; MS Calc .: 380, MS Found: 381 (M⁺+ H); temp.top. 123-124 ° C.

Example 27 (Comparative)

1- [3- (Difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1028]

<img file="PL2393360T3_D0262.tif" />

[1029] For a solution of 1- [3- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-yloyl] pyridazin-4 (1H) -one (crude, 993 mg, 2.96 mmol) in 20 ml methanol was added phenylhydrazine (480 mg, 4.44 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- [3- (difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (160 mg, 14% for two steps ) in the form of a yellow solid.

[1030] ¹H NMR (400 MHz, CDCl3): δ ppm 6.31 (s, 0.25 * 1H), 6.49 (s, 0.5 * 1H), 6.62 (t, J = 2.4 Hz, 1H), 6.68 (s, 0.25 * 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.79 (dq, J = 8.0, 0.8 Hz, 1H ), 7.09 (dd, J = 8.4, 1.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.72-7.48 (m, 6H) , 7.83 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.027 min; MS Calc .: 380, MS Found: 381 (M⁺+ H); temp.top. 159-160 ° C.

Example 28 (Comparative)

1- [4- (Difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1031]

255

<img file="PL2393360T3_D0263.tif" />

[1032] For a solution of 1- [4- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-yloyl] pyridazin-4 (1H) -one (crude, 747 mg, 2.22 mmol) in 20 ml methanol was added phenylhydrazine (360 mg, 3.33 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- [4- (difluoromethoxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one (190 mg, 22% for two steps ) in the form of a yellow solid.

[1033] ¹H NMR (400 MHz, CDCl3): δ ppm 6.35 (s, 0.25 * 1H), 6.54 (s, 0.5 * 1H), 6.72 (s, 0.25 * 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.82 (dd, J = 6.8, 2.0 Hz, 2H), 7.07 (d, J = 9.2 Hz, 2H ), 7.42-7.51 (m, 6H), 7.82 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.007 min; MS Calc .: 380, MS Found: 381 (M⁺+ H); temp.top. 175-176 ° C.

Example 29 (Comparative)

1- (2-Morpholin-4-ylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1034]

<img file="PL2393360T3_D0264.tif" />

[1035] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (2-morpholin-4-ylphenyl) pyridazin-4 (1H) -one (crude, 870 mg, 2.46 mmol) in 20 ml of methanol, phenylhydrazine (400 mg, 3.69 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (2-morpholin-4-ylphenyl) -3- (1256 phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (50 mg, 5% for two stages) as a yellow solid.

[1036] ¹H NMR (400 MHz, CDCl3): δ ppm 2.73 (t, J = 4.4 Hz, 4H), 3.70 (t, J = 4.4 Hz, 4H), 6.45 (dd, J = 8.0, 1.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.95-6.99 (m, 1H), 7.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.28-7.29 (m, 1H), 7.32-7.41 (m, 6H), 7.81 (d, J = 2.4 Hz , 1H), 8.27 (d, J = 7.6 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.641 min; MS Calc .: 399, MS Found: 400 (M⁺+ H); temp.top. 200-201 ° C.

Example 30 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1-pyridin-3-yl-pyridazin-4 (1H) -one [1037]

<img file="PL2393360T3_D0265.tif" />

[1038] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1-pyridin-3-pyridazin4 (1H) -one (crude, 260 mg, 0.98 mmol) in 20 ml of methanol was added phenylhydrazine ( 423 mg, 3.92 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3- (1-phenyl-1H-pyrazol-5-yl) -1-pyridin-3-yl-pyridazin-4 (1H) -one (60 mg, 19% for two steps) in forms of a yellow solid.

[1039] ¹H NMR (400 MHz, CDCl3): δ ppm 6.75 (d, J = 7.2 Hz, 1H), 7.00-7.03 (m, 1H), 7.22-7.26 (m, 1H), 7.39-7.50 (m, 6H), 7.82 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8, 26 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 4.8, 1.2 Hz, 1H); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.872 min; MS Calc .: 315, MS Found: 316 (M⁺+ H); temp.top. 176-177 ° C.

Example 31 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1-pyridin-4-yl-pyridazin-4 (1H) -one [1040]

257

<img file="PL2393360T3_D0266.tif" />

[1041] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1-pyridin-4-yl-pyridazin 4 (1H) -one (crude, 158 mg, 0.58 mmol) in 20 ml of methanol was added phenylhydrazine ( 253 mg, 2.34 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3- (1-phenyl-1H-pyrazol-5-yl) -1-pyridin-4-yl-pyridazin-4 (1H) -one (30 mg, 16% for two steps) in forms of a yellow solid.

[1042] ¹H NMR (400 MHz, CDCl3): δ ppm 6.72-6.75 (m, 3H), 7.31-7.52 (m, 6H), 7.82 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.50-8.52 (m, 2H); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.850 min; MS Calc .: 315, MS Found: 316 (M⁺+ H); temp.top. 202-203 ° C.

Example 32 (Comparative)

1- (2-Chloro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [1043]

<img file="PL2393360T3_D0267.tif" />

[1044] To a solution of 1- (2-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin 4 (1H) -one (crude, 636 mg, 2.10 mmol) in 20 ml methanol was added phenylhydrazine (907 mg, 8.40 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (2-chlorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (60 mg, 8% for two steps) in the form of a red gel.

[1045] ¹H NMR (400 MHz, CDCl3): δ ppm 6.63 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 -7.22 (m, 2H), 7.27-7.40 (m, 6H), 7.44-7.46 (m, 1H), 7.76 (d, J = 1.6 Hz,

258

1H), 7.91 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.662 min; MS Calc .: 348, MS Found: 349 (M⁺+ H); temp.top. 138-139 ° C.

Example 33 (Comparative)

3- [1- (1-Methylethyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1046]

<img file="PL2393360T3_D0268.tif" />

[1047] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (500 mg, 1.5 mmol) in ethanol ( 10 ml) isopropylhydrazine hydrochloride (246 mg, 2.2 mmol) and Et3N (0.41 ml, 3.0 mmol) were added. The mixture was stirred at 100 ° C for 5 hours. The mixture was diluted with 1N aqueous HCl, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 10/90 to 0/100) and recrystallized with AcOEt / i-Pr2O to give the title compound as a pale yellow solid (323 mg, 63%).

[1048] ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.43 (d, J = 6.4 Hz, 6H), 4.84 - 5.07 (m, 1H), 6.70 (d, J = 8 , 0 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 5.3 Hz, 2H), 8.04 - 8.13 (m, 1H), 8.14 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H). LC-MS (M⁺) 348.55; temp.top. 183-184 ° C.

Example 34 (Comparative)

3- [1- (2-Methylpropyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one [1049]

<img file="PL2393360T3_D0269.tif" />

259 [1050] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (500 mg, 1.5 mmol) in ethanol ( 10 mL) 2-methylpropylhydrazine hydrochloride (274 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol) were added. The mixture was stirred at 100 ° C for 5 hours. The mixture was diluted with 1N aqueous HCl, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 10/90 to 0/100) and recrystallized with AcOEt / i-Pr2O to give the title compound as a pale yellow solid (289 mg, 54%).

[1051] ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.73 (d, J = 6.8 Hz, 6 H), 2.12 (dt, J = 13.6, 6.8 Hz, 1H), 4.22 (d, J = 7.6 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H) , 7.55 (d, J = 1.9 Hz, 1H), 7.74 - 7.93 (m, 2H), 7.98 - 8.26 (m, 2H), 8.95 ( d, J = 7.6 Hz, 1H). LC-MS (M⁺) 362.77; temp.top. 120-121 ° C.

Example 35 (Comparative)

3- (1-Pyridin-2-yl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1052]

<img file="PL2393360T3_D0270.tif" />

[1053] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (800 mg, 2.4 mmol) in ethanol ( 20 ml) 2-hydrazinopyridine (388 mg, 3.6 mmol) and Et3N (0.66 ml, 4.7 mmol) were added. The mixture was stirred at 100 ° C for 5 hours. The mixture was diluted with water, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by HPLC and recrystallized from AcOEt / hexane to give the title compound as a pale yellow solid (460 mg, 51%).

[1054] ¹H NMR (300 MHz, DMSO-d6) δ ppm 6.57 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 7.18 - 7.42 (m, 1 H), 7.60 - 8.10 (m, 7H), 8.21 (d, J = 4.5 Hz, 1H), 8.99 (d, J = 8.3 Hz, 1H) . LC-MS (M⁺) 383.82; temp.top. 189-190 ° C.

Preparative HPLC was carried out under the conditions described below.

Column: Sepax HP-C18 (30 χ 50 mm S-10 μm)

Column temperature: 25 ° C

260

Mobile phase: (A) 0.1% TFA in distilled water, (B) 0.1% TFA in acetonitrile

Gradient: 0 min (A / B = 90/10)&gt; 1.20 min (A / B = 90/10)&gt; 4.75 min (A / B = 0/100)&gt; 7.80 min (A / B = 0/100)&gt; 7.90 min (A / B = 90/10)&gt; 9.00 min (A / B = 90/10)

Flow rate: 70 ml / min

Detector: UV 220 nm

Concentration: 80 mg / ml

Injection volume: 1250 μΐ

Example 36 (Comparative)

1- [3- (Methylsulfonyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1055]

<img file="PL2393360T3_D0271.tif" />

[1056] A mixture of 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one and 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) one (0.727 g, 2.02 mmol) in acetic acid (25 mL, 80% in water) was treated with potassium permanganate (0.500 g, 3.16 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. After this time, the reaction mixture was directly concentrated to remove acetic acid and neutralized with saturated sodium bicarbonate to pH = 7. After extraction with ethyl acetate (3 χ 100 mL), the combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 94: 6 methylene chloride: methanol) followed by crystallization from methanol and two subsequent purifications by preparative HPLC gave 1- [3- (methylsulfonyl) phenyl] -3- (1-phenyl-1H pyrazol-5-yl) pyridazin-4 (1H) -one (0.062 g, 8%) as a white solid. [1057]¹H NMR (500 MHz, DMSO-d6) δ ppm 3.26 (s, 3H), 6.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.26-7.29 (m, 1H), 7.39-7.42 (m, 3H), 7.44-7.48 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.87-7.90 (m, 1H), 8.01 (t, J = 2.0 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H); APCI MS m / z 393 [M + H]⁺; temp.top. 199-200 ° C.

Example 37 (Comparative)

1- [3- (1H-benzimidazol-2-yloxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pirydazyn4 (1H) -one

261 [1058]

<img file="PL2393360T3_D0272.tif" />

[1059] A mixture of 1- (3-hydroxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) one (0.113 g, 0.342 mmol) and 2-chlorobenzimidazole (0.075 g, 0 , 49 mmol) in Et3N (1 mL) was sealed and stirred at 120 ° C for 14 hours and then at 160 ° C for 64 hours. After this time, the reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodium bicarbonate solution (40 ml) and then with 2 N sodium hydroxide (3 χ 20 ml). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 1:19 methanol / methylene chloride) provided 1- [3- (1H-benzimidazol-2-yloxy) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -one (33 mg, 18%) as a pale yellow solid.

[1060] ¹H NMR (500 MHz, DMSO-d6) δ 6.65 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 7.12-7.19 (m, 4H), 7 , 25-7.34 (m, 5H), 7.37-7.46 (m, 3H), 7.47 (t, J = 8.2 Hz, 1H), 7.81 (d, J = 1 , 8 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H), 12.43 (s, 1H); APCI MS m / z 447 [M + H]⁺ ; temp.top. 149-150 ° C.

Example 38 (Comparative)

1- [3- (Methylsulfinyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1061]

<img file="PL2393360T3_D0273.tif" />

[1062] A mixture of 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one and 1- [3- (methylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) one (0.180 g, 0.50 mmol), sodium bicarbonate (0.168 g, 2.0 mmol) in methylene chloride (8 mL) was treated as with 3-chloroperbenzoic acid (0.140 g, 77%, 0.62 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. After this time, the reaction mixture was diluted with methylene chloride (20 mL), quenched with sodium thiosulfate (10%, 30 mL) and extracted with chloride

262 methylene (2 χ 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 1:10 methanol / methylene chloride) followed by preparative HPLC gave 1- [3- (methylsulfinyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -one (84 mg, 45%) as a white solid.

[1063] ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.85 (s, 3H), 6.70 (d, J = 7.9 Hz, 1H), 7.357.38 (m, 2H), 7.52- 7.56 (m, 2H), 7.76 (d, J = 7.7Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.917,93 (m, 2H), 8 , 00 (dt, J = 8.9, 1.1 Hz, 1H), 8.11-8.12 (m, 1H), 8.60 (d, J = 2.6 Hz, 1H), 8, 96 (d, J = 7.9 Hz, 1H); APCI MS m / z 377 [M + H]⁺.

Example 39 (Comparative)

1- [3- (1H-Benzimidazol-2-ylsulfonyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine4 (1H) -one [1064]

<img file="PL2393360T3_D0274.tif" />

[1065] Solution of a mixture of 1- [3- (1H-benzimidazol-2-ylsulfanyl) phenyl] -3- (1-phenyl1H-pyrazol-5-yl) pyridazin-4 (1H) -one and 1- [3- ( 1H-benzimidazol-2-ylsulfanyl) phenyl] -3 (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) -one (0.312 g, 0.68 mmol), 3-chloroperbenzoic acid (0.327 g 77% pure solid, 1.46 mmol) and sodium bicarbonate (0.227 g, 2.70 mmol) in dichloromethane (20 mL) was stirred for 2 hours at room temperature. After this time, the reaction mixture was diluted with dichloromethane (40 mL) and quenched with saturated sodium bisulfate solution (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 χ 60 mL) and ethyl acetate (2 χ 50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (silica gel, methylene chloride to 95: 5 dichloromethane / methanol), followed by crystallization from methanol and reverse phase preparative HPLC to give 1- [3- (1H-benzimidazol-2-sulfosyl) ) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (0.005 g, 2%) as a white solid.

[1066] ¹H NMR (500 MHz, DMSO-d6) δ ppm 6.64 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.25-7, 31 (m, 1H), 7.33-7.42 (m, 6H), 7.44 (dd, J = 2.4, 8.2 Hz, 1H), 7.64-7.75

263 (m, 3H), 7.83 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 8.14 (t, J = 1.9 Hz , 1H), 8.91 (d, J = 7.9 Hz, 1H), 14.17 (br s, 1H); ESI MS m / z 495 [M + H]⁺; temp.top. 160-161 ° C.

Example 40 (Comparative)

3- (4-Phenyl-4H-1,2,4-triazol-3-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1067]

<img file="PL2393360T3_D0275.tif" />

[1068] A solution of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbohydrazide (0.2 g, 0.67 mmol) and N, N-dimethylformamide dimethyl acetal (0.09 mL , 0.67 mmol) in acetonitrile (2 mL) was heated at 55 ° C for 45 minutes. After this time, acetic acid (2 mL) and aniline (0.06 mL, 0.66 mmol) were added and the temperature was increased to 125 ° C for an additional 2 hours. During this time, acetonitrile was distilled off. The reaction mixture was then concentrated to a dark residue and the crude product was purified by column chromatography (silica gel, ethyl acetate to 4: 1 ethyl acetate / methanol) to obtain 3- (4-phenyl-4H1,2,4-triazol-3-yl ) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.137 g, 53%) as a pale yellow oil which crystallized on standing.

[1069] ¹H NMR (300 MHz, CDCl3) δ ppm 6.67 (1H, d, J = 8.0 Hz), 7.30-7.41 (2H, m), 7.41-7.52 (3H, m ), 7.57-7.72 (4H, m), 8.28 (1H, d, J = 8.0 Hz), 8.43 (1H, s); APCI MS m / z 384 [C19H12F3N5O + H]⁺; temp.top. 103-104 ° C.

Example 41 (Comparative)

3- (5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine4 (1H) -one [1070]

<img file="PL2393360T3_D0276.tif" />

[1071] A solution of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbohydrazide (0.207 g, 0.69 mmol) and N, N-dimethylacetamide dimethyl acetal (0.1 mL, 0 , 68 mmol) in acetonitrile (2 ml) was heated at 60 ° C for 2.5

264 hours. After this time, acetic acid (2 mL) and aniline (0.06 mL, 0.66 mmol) were added and the temperature was increased to 125 ° C for an additional 2 hours. During this time, acetonitrile was distilled off. The reaction mixture was then concentrated to a dark residue and the crude product was purified by column chromatography (silica gel, ethyl acetate to 4: 1 ethyl acetate / methanol) to obtain a yellow solid which was recrystallized from ethyl acetate / hexanes to give 3- (5- methyl-4-phenyl-4H-1,2,4-triazol-3-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.126 g, 46%) in the form of pale yellow crystals.

[1072] ¹H NMR (300 MHz, CDCl3) δ ppm 2.40 (s, 3H), 6.63 (d, J = 8.0 Hz, 1H), 7.287.36 (m, 2H), 7.41-7, 52 (m, 3H), 7.56-7.71 (m, 4H), 8.20 (d, J = 8.1 Hz, 1H); APCI MS m / z 398 [M + H]⁺; temp.top. 191-192 ° C.

Example 42 (Comparative)

3- (1-Phenyl-1H-1,2,4-triazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1073]

<img file="PL2393360T3_D0277.tif" />

[1074] A solution of N - [(dimethylamino) methylidene] -4-oxo-1- [3- (trifluoromethyl) phenyl] 1,4-dihydropyridazine-3-carboxamide (0.119 g, 0.35 mmol) in acetic acid (5 , 0 ml) treated with phenylhydrazine (0.070 ml, 0.71 mmol). The resulting solution was heated under microwave heating at 120 ° C for 10 minutes. At this time, the reaction mixture was cooled to room temperature and the crude product was purified by flash column chromatography (silica gel, ethyl acetate to 85:15 ethyl acetate / methanol) to obtain a colorless solid which was recrystallized from ethyl acetate / hexanes to obtain 0.126 g (46%) 3- (1-phenyl-1H-1,2,4-triazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one in the form of colorless crystals.

[1075] ¹H NMR (300 MHz, CDCl3) δ ppm 6.75 (d, J = 8.1 Hz, 1H), 7.38-7.49 (m, 5H), 7.49-7.56 (m, 2H ), 7.56-7.70 (m, 2H), 8.17-8.31 (m, 2H); APCI MS m / z 384 [M + H]⁺; temp.top. 167-168 ° C.

Example 43 (Comparative)

3- (1-Phenyl-1H-tetrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

265 [1076]

<img file="PL2393360T3_D0278.tif" />

[1077] Solution of 3- [1H-benzotriazol-1-yl (phenylimino) methyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.094 g, 0.20 mmol), sodium azide (0.030 g, 0.46 mmol) and tetrabutylammonium bromide (0.015 g, 0.047 mmol) in methylene chloride (5 mL) and water (5 mL) were treated with trifluoroacetic acid (0.040 mL, 0.52 mmol) and stirred 24 hours in room temperature. After this time, the organic layer was separated and the aqueous layer was extracted with methylene chloride (3 25 ml). The combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried (MgSO 4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 80:20 hexanes / ethyl acetate to ethyl acetate) to obtain an off-white solid which was recrystallized from ethyl acetate / hexanes to obtain 0.034 g (56%) 3- (1 -phenyl-1H-tetrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one in the form of colorless crystals.

[1078] ¹H NMR (300 MHz, CDCl3) δ ppm 6.76 (d, J = 8.0 Hz, 1H), 7.43-7.59 (m, 5H), 7.59-7.75 (m, 4H ), 8.42 (d, J = 8.0 Hz, 1H); APCI MS m / z 385 [M + H]⁺; temp.top. 172173 ° C.

Example 44 (Comparative)

3- (1-Phenyl-1H-pyrazol-5-yl) -1- (4-piperidin-1-ylphenyl) pyridazin-4 (1H) -one [1079]

<img file="PL2393360T3_D0279.tif" />

[1080] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- (4-piperidin-1-ylphenyl) pyridazin-4 (1H) -one (crude, 700 mg, 1.99 mmol) in 20 ml of methanol, phenylhydrazine (858 mg, 7.94 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3- (1-phenyl-1H-pyrazol-5-yl) -1- (4266 piperidin-1-ylphenyl) pyridazin-4 (1H) -one (30 mg, 4% for two stages) as a yellow solid.

[1081] ¹H NMR (400 MHz, CDCl3): δ ppm 1.51-1.60 (m, 2H), 1.67-1.70 (m, 4H), 3.18 (t, J = 5.6 Hz, 4H), 6.65-6.70 (m, 3H), 6.74-6.77 (m, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.42-7 , 45 (m, 5H), 7.79 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.532 min; MS Calc .: 397, MS Found: 398 (M⁺+ H).

Example 45 (Comparative)

1- (4-Cyclohexylphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1082]

<img file="PL2393360T3_D0280.tif" />

[1083] To a solution of 1- (4-cyclohexylphenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one (crude, 500 mg, 1.42 mmol) in 20 ml methanol phenylhydrazine (615 mg, 5.70 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- (4-cyclohexylphenyl) -3- (1-phenyl 1H-pyrazol-5-yl) pyridazin-4 (1H) -one (170 mg, 30% for two steps) as yellow solid.

[1084] ¹H NMR (400 MHz, CDCl3): δ ppm 1.23-1.44 (m, 5H), 1.75-1.84 (m, 5H), 2.472.53 (m, 1H), 6.69- 6.73 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 7.38-7.49 (m, 6H), 7.79 (d, J = 2.0 Hz , 1H), 8.14 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 40% water and 60% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.358 min; MS Calc .: 396, MS Found: 397 (M⁺+ H).

Example 46 (Comparative)

4- [4-Oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] benzonitrile [1085]

267

<img file="PL2393360T3_D0281.tif" />

CN [1086] To a solution of 4- {3- [3- (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) yl} benzonitrile (crude, 340 mg, 1.16 mmol) in 20 ml methanol phenylhydrazine (500 mg, 4.62 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4- [4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] benzonitrile (18 mg, 4% for two steps) in forms of a yellow solid.

[1087] ¹H NMR (400 MHz, CDCl3): δ ppm 6.74 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 7.40-7.52 (m, 5H), 7.57 (dd, J = 8.8, 2.0 Hz, 2H), 7.81 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 80% water and 20% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.077 min; MS Calc .: 339, MS Found: 340 (M⁺+ H).

Example 47 (Comparative)

1- [4- (Methylsulfonyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one [1088]

<img file="PL2393360T3_D0282.tif" />

SO₂Me [1089] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [4- (methylsulfonyl) phenyl] pyridazin-4 (1H) -one (crude, 615 mg, 1.77 mmol) in 20 ml of methanol, phenylhydrazine (765 mg, 7.08 mmol) was added. The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- [4- (methylsulfonyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (42 mg, 6% for two steps ) in the form of a yellow solid.

268 [1090] ¹H NMR (400 MHz, DMSO-d6): δ ppm 3.26 (s, 3H), 6.69 (d, J = 8.0 Hz, 1H), 7.27-7.30 (m, 3H) , 7.41-7.43 (m, 2H), 7.48-7.52 (m, 3H), 7.84-7.89 (m, 3H), 8.94 (d, J = 8, 0 Hz, 1H); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95%

CH3CN in 6 minutes, finally under these conditions for 0.5 min.) Purity is&gt; 90%,

Rt = 3.102 min; MS Calc .: 392, MS Found: 393 (M⁺+ H).

Example 48 (Comparative)

1- [4- (Morpholin-4-ylsulfonyl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) on [1091]

<img file="PL2393360T3_D0283.tif" />

[1092] To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [4- (morpholin-4-ylsulfonyl) phenyl] pyridazin-4 (1H) -one (crude, 355 mg, 0, 85 mmol) in 20 mL methanol was added phenylhydrazine (367 mg, 3.40 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1- [4- (morpholin-4-ylsulfonyl) phenyl] 3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one (60 mg , 15% for two stages) as a yellow solid.

[1093] ¹H NMR (400 MHz, CDCl3): δ ppm 2.97 (t, J = 4.8 Hz, 4H), 3.74 (t, J = 4.8 Hz, 4H), 6.73 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 7.2, 1.6 Hz, 2H), 7.39-7.48 (m, 6H), 7.61-7.64 ( m, 2H), 7.80 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 80% water and 20% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 3.035 min; MS Calc .: 463, MS Found: 464 (M⁺+ H).

Example 49 (Comparative)

4- [4-Oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] benzamide [1094]

269

<img file="PL2393360T3_D0284.tif" />

CONH₂ [1095] To a solution of 4- {3- [3- (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) yl} benzamide (crude, 682 mg, 2.19 mmol) in 20 mL methanol was added phenylhydrazine (946 mg, 8.76 mmol). The mixture was heated to reflux for 4 hours and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N aqueous HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4- [4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] benzamide (50 mg, 6% for two steps ) in the form of a yellow solid.

[1096] ¹H NMR (400 MHz, CDCl3): δ ppm 6.75 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 7.25-7.26 (m, 1H), 7.41-7.49 (m, 5H), 7.74 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 2.0 Hz, 1H) , 8.23 ​​(d, J = 8.0 Hz, 1H); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 minutes, finally under these conditions for 0.5 min) purity is&gt; 95%, Rt = 2.663 min; MS Calc .: 357, MS Found: 358 (M⁺+ H).

Example 50

5-Methyl-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1097]

<img file="PL2393360T3_D0285.tif" />

[1098] Microwave vial containing 3- [3- (dimethylamino) prop-2-enoyl] -5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.215 g, 0.61 mmol ) and phenylhydrazine (0.24 mL, 2.44 mmol) in acetic acid (3 mL) was heated at 120 ° C for 10 minutes. The crude material was concentrated and dissolved in ethyl acetate (20 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3 x 10 mL), dried (Na2SO4), filtered and concentrated to a crude residue. The residue was purified by flash column chromatography (silica gel; 35:65 ethyl acetate / hexanes to ethyl acetate) to give 5-methyl-3- (1270 phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.0545 g, 23%) as an off-white solid.

[1099] ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.06 (s, 3H), 7.22 (d, J = 2.1 Hz, 1H), 7.37-7.48 (m, 6H), 7.52 (s, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.68-7.71 (m, 1H), 7.83 (d, J = 1.8 Hz , 1H) 9.00 (s, 1H); APCI MS m / z 397 [M + H]⁺; temp.top. 147-150 ° C.

Example 51 (Comparative)

3- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1100]

<img file="PL2393360T3_D0286.tif" />

[1101] Solution of 3- [3- (dimethylamino) but-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (0.270 g, 0.77 mmol) and phenylhydrazine (0.200 ml, 2.0 mmol) in acetic acid (5.0 ml) was heated under microwave conditions at 120 ° C for 10 minutes. After this time, the reaction mixture was cooled to room temperature and concentrated on silica gel. The crude product was purified by column chromatography (silica gel, 50:50 ethyl acetate / hexanes to ethyl acetate) to separate the two isomers, followed by reverse phase preparative HPLC and crystallization from diethyl ether to give 3- (3-methyl-1) -phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.048 g, 16%) as a white solid. ¹H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H), 6.73 (d, J = 7.9 Hz, 1H), 6.99 (dd, J = 1.7, 8.1 Hz, 1H), 7.18 (br s, 1H), 7.21 (s, 1H), 7.30-7.49 (m, 6H), 7.55 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H); APCI MS m / z 397 [M + H]⁺; temp.top. 167-168 ° C.

Example 52

1- (2-Fluoro-phenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [1102]

<img file="PL2393360T3_D0287.tif" />

271 [1103] A solution of 3-acetyl-1- (2-fluorophenyl) -5-methoxypyridazin-4 (1H) -one (1.89 g, 7.2 mmol) in N, N-dimethylformamide dimethyl acetal (20 ml) was heated under reflux at reflux for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. [1104] A solution of the residue and phenylhydrazine (2.34 mL, 21.6 mmol) in AcOH (20 mL) was refluxed at reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (1/2) and recrystallized from MeOH / H2O to give the title compound (1.53 g, 59% yield) as off-white crystals: m.p. 163-165 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 6.43 (1H, dt, J = 1.5, 7.9 Hz), 6.98-7.04 (1H, m), 7.18 (1H, ddd, J = 1.1, 8.3, 11.3 Hz), 7.28-7.46 (7H, m), 7.78 (1H, d, J = 1.9 Hz), 7.81 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 363 [M + H]⁺. Anal. calc. for C20H15FN4O2: C, 66.29; H, 4.17; N, 15.46. Found: C, 66.09; H, 4.22; N, 15.42.

Example 53

1- [2- (Difluoromethoxy) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine4 (1H) -one [1105]

<img file="PL2393360T3_D0288.tif" />

[1106] A solution of 1- [2- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazin-4 (1H) -one (0.50 g, 1.369 mmol) and phenylhydrazine ( 0.269 ml, 2.74 mmol) in AcOH (5 ml) was heated to reflux for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed sequentially with 1 M aqueous HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (7 / 3-0 / 10) to obtain the title compound (0.38 g, 68%

272 yield) as an off-white amorphous solid: ¹H NMR (300 MHz, CDCl3): δ ppm 3.88 (3H, s), 6.37 (1H, t, J = 72.3 Hz), 6.57 (1H, dd, J = 8.1, 1.7 Hz), 7.09-7.16 (1H, m), 7.22-7.25 (2H, m), 7.34-7.42 (6H, m), 7.76-7 , 78 (2H, m). LC-MS (ESI) m / z 411 [M + H]⁺. Anal. Calculate. for C21H16F2N4O3: C, 61.15; H, 4.07; N, 13.79. Found: C, 61.23; H, 4.11; N, 13.71.

Example 54

5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine 4 (1H) -one [1107]

<img file="PL2393360T3_D0289.tif" />

[1108] Solution of 3- [3- (dimethylamino) prop-2-enoyl] -5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (3.41 g, 9.29 mmol) and phenylhydrazine (1.83 mL, 18.6 mmol) in AcOH (25 mL) was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane / AcOEt to give the title compound (2.70 g, 71% yield) as colorless crystals: m.p. 139-141 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 7.05 (1H, dd, J = 1.9, 7.9 Hz), 7.19 (1H, s), 7 , 34-7.47 (7H, m), 7.56 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 7.92 (1H, s). LC-MS (ESI) m / z 413 [M + H]⁺. Anal. calc. for C21H15F3N4O2: C, 61.17; H, 3.67; N, 13.59. Found: C, 61.15; H, 3.65; N, 13.57.

Example 55

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) on [1109]

273

<img file="PL2393360T3_D0290.tif" />

[1110] A mixture of 3-acetyl-1- (2-fluoro-4-iodophenyl) -5-methoxypyridazin-4 (1H) -one (2.02 g, 5.2 mmol) and N, N-dimethylformamide dimethyl acetal ( 30 ml) was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. [1111] A solution of the residue and phenylhydrazine (1.54 mL, 15.6 mmol) in AcOH (20 mL) was refluxed at reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (1.14 g, 45% yield) as pale yellow crystals: m.p. 194-196 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 6.04 (1H, t, J = 8.5 Hz), 7.30-7.47 (7H, m), 7 , 54 (1H, dd, J = 1.9, 10.6 Hz), 7.76 (1H, d, J = 2.3 Hz), 7.78 (1H, d, J = 2.3 Hz) . LC-MS (ESI) m / z 489 [M + H]⁺. Anal. calc. for C20H14FIN4O2: C, 49.20; H, 2.89; N, 11.47. Found: C, 48.94; H, 3.01; N, 11.54.

Example 56

1- [2-Fluoro-4- (trifluoromethyl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one [1112]

<img file="PL2393360T3_D0291.tif" />

[1113] A mixture of 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (244 mg, 0.50 mmol) , FSO2CF2CO2Me (0.318 mL, 2.5 mmol), HMPA (0.435 mL, 2.5 mmol) and CuI (114 mg, 0.6 mmol) in DMF (2.5 mL) were stirred for 24 hours at 90 ° C in the atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under

274 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 (71.7 mg, 33% yield) as off-white crystals: m.p. 169-171 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.42-6.47 (1H, m), 7.22-7.26 (1H, m), 7.37- 7.49 (7H, m), 7.80 (1H, d, J = 1.9 Hz), 7.84 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 431 [M + H]⁺. Anal. calc. for C21H14F4N4O2: C, 58.61; H, 3.28; N, 13.02. Found: C, 58.50; H, 3.36; N, 12.93.

Example 57

1- (2-Fluoro-4-morpholin-4-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one [1114]

<img file="PL2393360T3_D0292.tif" />

[1115] Suspension of 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (244 mg, 0.5 mmol), morpholine (0.053 ml, 0.6 mmol), Pd2 (dba) 3 (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol) and NaOtBu (67.3 mg , 0.7 mmol) in

1,4-dioxane (2.5 mL) was stirred for 2 hours at 90 ° C under an atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH / H2O to give the title compound (148 mg, 66% yield) as off-white crystals: m.p. 226-228 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.16-3.19 (4H, m), 3.83-3.87 (4H, m), 3.89 (3H, s), 6.31 ( 1H, t, J = 9.0 Hz), 6.45 (1H, dd, J = 2.6, 9.0 Hz), 6.58 (1H, dd, J = 2.6, 14.7 Hz ), 7.26 (1H, d, J = 1.9 Hz), 7.33-7.45 (5H, m), 7.74 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 448 [M + H]⁺Anal. calc. for C24H22FN5O3: C, 64.42; H, 4.96; N, 15.65. Found: C, 64.33; H, 4.98; N, 15.59.

275

Example 58

5-Hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine 4 (1H) -one [1116]

<img file="PL2393360T3_D0293.tif" />

[1117] TMSCl (3.17 mL, 25 mmol) was added at room temperature to a solution of NaI (3.75 g, 25 mmol) in CH3CN (150 mL). After stirring for 30 minutes, 5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (2) was added to the resulting suspension. , 06 g, 5 mmol). The mixture was stirred for 30 minutes at room temperature and then heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with hexane / AcOEt (1/1) and recrystallized from MeOH / H2O to give the title compound (1.68 g, 84% yield) as a colorless powder: m.p. 246-248 ° C;¹H NMR (300 MHz, DMSO-d6): δ ppm 7.17 (1H, d, J = 1.9 Hz), 7.33-7.46 (5H, m), 7.53-7.64 ( 3H, m), 7.71 (1H, d, J = 7.5 Hz), 7.83 (1H, d, J = 1.9 Hz), 8.83 (1H, s). Anal. calc. for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.09; H, 3.33; N, 14.02.

Example 59

5-Ethoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1118]

<img file="PL2393360T3_D0294.tif" />

[1119] Suspension of 5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol ), iodoethane (0.040 mL, 0.50 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 hours at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under

276 reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (1/1) to give the title compound (94.1 mg, 88% yield) as an off-white amorphous solid:¹H NMR (300 MHz, CDCl3): δ ppm 1.52 (3H, t, J = 6.8 Hz), 4.21 (2H, q, J = 6.8 Hz), 7.03 (1H, dd , J = 1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J = 7.9 Hz) , 7.80 (1H, d, J = 1.9 Hz), 7.94 (1H, s). LC-MS (ESI) m / z 427 [M + H]⁺. Anal. calc. for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.82; H, 4.15; N, 13.17.

Example 60

5- (1-Methylethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1120]

<img file="PL2393360T3_D0295.tif" />

[1121] Suspension of 5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol ), 2-iodopropane (0.050 mL, 0.50 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 hours at 60 ° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (1/1) and crystallized from hexane / AcOEt to give the title compound (79.5 mg, 72% yield) as colorless bars: m.p. 137-139 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 1.38 (6H, d, J = 6.4 Hz), 4.96-5.09 (1H, m), 7.05 (1H, dd, J = 1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7, 80 (1H, d, J = 1.9 Hz), 8.01 (1H, s). LC-MS (ESI) m / z 441 [M + H]⁺. Anal. calc. for C23H19F3N4O2: C, 62.72; H, 4.35; N, 12.72. Found: C, 62.74; H, 4.40; N, 12.81.

Example 61

5- (Cyclopropylmethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1122]

277

<img file="PL2393360T3_D0296.tif" />

[1123] Suspension of 5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol ), (bromomethyl) cyclopropane (0.048 mL, 0.50 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 hours at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (1/1) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless bars: m.p. 72-78 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J = 7.2 Hz), 7.04 (1H, dd, J = 2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7 , 46 (7H, m), 7.55 (1H, d, J = 7.9 Hz),

7.80 (1H, d, J = 1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m / z 453 [M + H]⁺. Anal. calc. for

C24H19F3N4O2A5H2O: C, 62.47; H, 4.37; N, 12.14. Found: C, 62.19; H, 4.41; N

12,15.

Example 62

5- (Difluoromethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1124]

<img file="PL2393360T3_D0297.tif" />

[1125] A mixture of 5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (398 mg, 1.0 mmol ), CF2ClCO2Na (305 mg, 2.0 mmol), K2CO3 (207 mg, 1.5 mmol), DMF (2 mL) and H2O (0.4 mL) were stirred for 6 hours at 100 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (3/1) and crystallized from hexane / AcOEt to give the title compound (267 mg, 59% yield) as colorless bars:

278 temp.top. 132-134 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 7.06 (1H, dd, J = 2.3, 8.3 Hz), 7.16-7.66 (10H, m), 7.82 (1H, d, J = 1.9 Hz), 8.33 (1H, s). LC-MS (ESI) m / z 449 [M + H]⁺. Anal. calc. for C21H13F5N4O2: C, 56.26; H, 2.92; N, 12.50. Found: C, 55.98; H, 2.82; N, 12.43.

Example 63

1- (2-Fluoro-phenyl) -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -pyridazin-4 (1H) -one [1126]

<img file="PL2393360T3_D0298.tif" />

[1127] TMSCl (1.27 mL, 10 mmol) was added at room temperature to a solution of NaI (1.50 g, 10 mmol) in CH3CN (60 mL). After stirring for 30 minutes, 1- (2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one (0.725 g, 2 mmol) was added to the resulting suspension. . The mixture was stirred for 30 minutes at room temperature and then heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with hexane / AcOEt (1/1) and recrystallized from MeOH / H2O to give the title compound (0.648 g, 93% yield) as off-white bars: m.p. 218-220 ° C;¹H NMR (300 MHz, DMSO-d6): δ ppm 6.99 (1H, d, J = 1.9 Hz), 7.10 (1H, dt, J = 1.5, 7.9 Hz), 7 , 21-7.26 (1H, m), 7.32-7.54 (7H, m), 7.80 (1H, d, J = 1.9 Hz), 8.44 (1H, d, J = 2.6 Hz). Anal. calc. for C19H13FN4O2: C, 65.51; H, 3.76; N, 16.08. Found: C, 65.73; H, 3.88; N, 16.24.

Example 64

5- (Difluoromethoxy) -1- (2-fluoro-phenyl) -3- (1-phenyl-1H-pyrazol-5-yl) -pyridazine-4 (1H) -one [1128]

<img file="PL2393360T3_D0299.tif" />

[1129] A mixture of 1- (2-fluorophenyl) -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (557 mg, 1.6 mmol), CF2ClCO2Na (488 mg, 3.2 mmol), K2CO3 (332

279 mg, 2.4 mmol), DMF (3 mL) and H2O (0.6 mL) were stirred overnight at 100 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (2/1) and crystallized from hexane / AcOEt to give the title compound (485 mg, 76% yield) as colorless bars: m.p. 109114 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 6.46 (1H, dd, J = 1.5, 7.9 Hz), 7.00-7.06 (1H, m), 7.08-7, 59 (9H, m), 7.80 (1H, d, J = 1.9 Hz), 8.20 (1H, s). LC-MS (ESI) m / z 399 [M + H]⁺Anal. calc. for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.50; H, 3.41; N, 14.20.

Example 65

5- (2-Methoxyethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1130]

<img file="PL2393360T3_D0300.tif" />

[1131] Suspension of 5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol ), 2-bromoethyl methyl ether (0.070 ml,

0.75 mmol) and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 hours at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (1/2) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: ¹H NMR (300 MHz, CDCl3): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 ( 1H, dd, J = 1.9, 7.9 Hz), 7.20 (1H, s), 7.347.45 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 8.29 (1H, s). LC-MS (ESI) m / z 457 [M + H] +. Anal. calc. for C23H19F3N4O3OB5H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.

280

Example 66

5- (Methoxymethyl) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1132]

<img file="PL2393360T3_D0301.tif" />

[1133] A solution of 3-acetyl-5- (methoxymethyl) -1- [3- (trifluoromethyl) phenyl] pyridazin 4 (1H) -one (1.39 g, 4.26 mmol) in N, N-dimethylformamide dimethyl acetal ( 15 ml) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt three times. The combined extracts were washed with brine, dried over MgSO 4 and concentrated under reduced pressure.

[1134] A solution of the residue and phenylhydrazine (1.18 mL, 12 mmol) in MeOH (15 mL) was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane / AcOEt (2/1) and recrystallized from hexane / AcOEt to give the title compound (759 mg, 42% yield) as a pale yellow solid: m.p. 137-139 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.55 (3H, s), 4.53 (2H, d, J = 1.1 Hz), 7.06 (1H, dd, J = 1.9, 7.9 Hz), 7.19 (1H, s), 7.35-7.45 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.81 (1H, d, J = 1.9 Hz), 8.34 (1H, t, J = 1.1 Hz). LC-MS (ESI) m / z 427 [M + H]⁺. Anal. calc. for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.60; H, 4.05; N, 13.07.

Example 67

5-Bromo-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1135]

281

<img file="PL2393360T3_D0302.tif" />

[1136] A mixture of 3-acetyl-5-bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (332 mg, 0.92 mmol) and N, N-dimethylformamide dimethyl acetal (3, 3 ml) was heated to reflux for 1 hour. The mixture was concentrated in vacuo. AcOH (3.3 mL) and phenylhydrazine (0.181 mL, 1.84 mmol) were added to the residue. The mixture was heated to reflux for 90 minutes. Phenylhydrazine (0.091 mL, 0.92 mmol) was added to the mixture. The mixture was heated to reflux for 90 minutes. The mixture was diluted with 1 M aqueous HCl, extracted with AcOEt, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated in vacuo and purified by basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and by HPLC to give the title compound (151 mg, 35% yield) as a white solid: m.p. 145-146 ° C. ¹H NMR (DMSO-d6, 300 MHz): δ ppm 7.27 (1H, d, J = 1.9 Hz), 7.35-7.52 (6H, m), 7.54-7.64 ( 2H, m), 7.73 (1H, d, J = 8.0 Hz), 7.85 (1H, d, J = 1.9 Hz), 9.52 (1H, s). Anal. calc. for C20H12BrF3N4O: C, 52.08; H, 2.62; N, 12.15. Found: C, 52.07; H, 2.75; N, 12.28. [1137] Preparative HPLC was carried out under the conditions described below.

Column: Waters SunFire Column C18 (30 χ 50 mm S-5μm)

Column temperature: 25 ° C

Mobile phase: (A) 0.1% TFA in distilled water, (B) 0.1% TFA in acetonitrile Gradient: 0 min (A / B = 60/40)&gt; 1.20 min (A / B = 60 / 40)&gt; 4.75 min (A / B = 0/100)&gt; 7.75 min (A / B = 0/100)&gt; 7.85 min (A / B = 60/40)&gt; 8.50 min ( A / B = 60/40)

Flow rate: 70 ml / min

Detector: UV 220 nm

Concentration: 98 mg / ml

Injection volume: 825 μΐ

Example 68

1- [4- (Benzyloxy) -2-fluoro-phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -pyridazine-4 (1H) -one [1138]

282

<img file="PL2393360T3_D0303.tif" />

[1139] A solution of 3-acetyl-1- [4- (benzyloxy) -2-fluorophenyl] -5-methoxypyridazin-4 (1H) one (5.82 g, 15.8 mmol) in N, N-dimethylformamide dimethyl acetal (50 ml) was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.

[1140] A solution of the residue and phenylhydrazine (3.11 mL, 31.6 mmol) in AcOH (50 mL) was refluxed at reflux for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed sequentially with 1 M aqueous HCl, 1 M aqueous NaOH and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with AcOEt and then purified by basic silica gel column chromatography eluting with THF. Recrystallization from MeOH / H2O gave the title compound (5.57 g, 75% yield) as a pale yellow solid: m.p. 181-183 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 5.06 (2H, s), 6.35 (1H, t, J = 9.0 Hz), 6.60 (1H , ddd, J = 1.1, 2.6, 9.0 Hz), 6.74 (1H, dd, J = 2.6, 12.8 Hz), 7.28 (1H, d, J = 1 , 9 Hz), 7.31-7.45 (10H, m), 7.72 (1H, d, J = 2.6 Hz), 7.78 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 469 [M + H]⁺. Anal. calc. for C27H21FN4O3: C, 69.22; H, 4.52; N, 11.96. Found: C, 69.04; H, 4.60; N, 11.98.

Example 69 (Comparative)

6-Hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine 4 (1H) -one [1141]

<img file="PL2393360T3_D0304.tif" />

[1142] Chlorotrimethylsilane (0.46 mL, 3.6 mmol) was added to a solution of sodium iodide (0.55 g, 0.73 mmol) in MeCN (20 mL) at room temperature. After stirring for 30 minutes, 5-methoxy-6- (1-phenyl-1H-pyrazol-5-yl) -2- [3283 (trifluoromethyl) phenyl] pyridazin-3 (2H) -one (0, 30 g, 0.73 mmol). The mixture was stirred at room temperature for 1 hour and then heated under reflux for 3 hours. After cooling to room temperature, the mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was washed with diisopropyl ether / hexane and recrystallized from AcOEt / hexane to give the title compound (0.21 g, 73% yield) as white crystals: m.p. 241-243 ° C;¹H NMR (300 MHz, DMSO-d6): δ ppm 6.16 (1H, s), 6.88 (1H, d, J = 1.9 Hz), 7.36-7.42 (3H, m) , 7.45-7.54 (4H, m), 7.59 (1H, t, J = 7.9 Hz), 7.70 (1H, d, J = 7.9 Hz), 7.82 ( 1H, d, J = 1.9 Hz), 12.23 (1H, brs). LC-MS (ESI) m / z 399 [M + H]⁺. Anal. calc. for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.35; H, 3.37; N, 14.10.

Example 70 (Comparative)

3- [1-Phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1143]

<img file="PL2393360T3_D0305.tif" />

[1144] To a solution of ethyl trifluoroacetate (0.139 ml, 1.17 mmol) in methyl tert-butyl ether (1 ml) was added NaOMe (28% in MeOH, 245 mg, 1.27 mmol) at room temperature. To the mixture was added a solution of 3-acetyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (300 mg, 1.06 mmol) in THF (1.5 mL) and methyl tert-butyl ether (1 , 5 ml) at room temperature. The mixture was stirred at room temperature for 2 days. The mixture was diluted with 1 M aqueous HCl, extracted with AcOEt, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Phenylhydrazine (0.209 mL, 2.12 mmol) and AcOH (3.5 mL) were added to the residue. The mixture was heated to reflux for 90 minutes. The mixture was diluted with 1 M aqueous HCl, extracted with AcOEt, washed with aqueous NaHCO3, dried over MgSO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 50/50 to 0 / 100), crystallized

284 with AcOEt / hexane and purified by HPLC to give the title compound (9.6 mg, 2% yield) as a white solid: m.p. 190-191 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.73 (1H, d, J = 7.9 Hz), 7.37-7.81 (10H, m), 8.97 (1H, d, J = 8.3 Hz). Anal. calc. for C21H12F6N4O: C, 56.01; H, 2.69; N, 12.44. Found: C, 55.70; H, 2.81; N, 12.23.

[1145] Preparative HPLC was carried out under the conditions described below.

Column: Waters SunFire Column C18 (30 χ 50 mm S-5μm)

Column temperature: 25 ° C

Mobile phase: (A) 0.1% TFA in distilled water, (B) 0.1% TFA in acetonitrile Gradient: 0 min (A / B = 52/48)&gt; 10.00 min (A / B = 52 / 48)&gt; 10.50 min (A / B = 0/100)&gt; 12.50 min (A / B = 0/100)&gt; 12.60 min (A / B = 52/48)&gt; 13.00 min ( A / B = 52/48) Flow rate: 20 ml / min

Detector: UV 220 nm

Concentration: 100 mg / ml

Injection volume: 100 μΐ

Example 71 (Comparative)

3- (4-Methyl-1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1146]

<img file="PL2393360T3_D0306.tif" />

[1147] To a suspension of 3-propanoyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (384 mg, 1.30 mmol) in methyl formate (3.8 mL) was added NaOMe (28% in MeOH, 326 mg, 1.69 mmol) at room temperature. The mixture was stirred at room temperature for 3.5 hours. The mixture was diluted with water and 1 M aqueous HCl, extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and crystallized with AcOEt / hexane. Phenylhydrazine (0.405 mL, 4.12 mmol) and MeOH (6.7 mL) were added to the solid. The mixture was heated to reflux for 3.5 hours. The mixture was diluted with 1 M aqueous HCl, extracted with AcOEt, washed with saturated aqueous NaHCO3, dried over Na2SO4.

285 filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and crystallized with AcOEt / heptane to give the title compound (161 mg, 39% yield) as a light yellow solid : temp. 208-211 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 2.09 (3H, s), 6.62 (1H, d, J = 8.0 Hz), 7.26-7.35 (3H, m) , 7.35-7.44 (2H, m), 7.64-7.85 (5H, m), 8.95 (1H, d, J = 8.2 Hz). Anal. calc. for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.46; H, 3.92; N, 13.98.

Example 72 (Comparative)

3- (4-Fluoro-1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1148]

<img file="PL2393360T3_D0307.tif" />

[1149] A mixture of 3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (49.0 mg, 0.128 mmol) and selectfluor (45, 4 mg, 0.128 mmol) in MeCN (1 mL) was stirred at room temperature for 6 days. Selectfluor (45.4 mg, 0.128 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 day. Selectfluor (45.4 mg, 0.128 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 day. Selectfluor (45.4 mg, 0.128 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 day. Selectfluor (272 mg, 0.768 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 3 days. The mixture was diluted with brine, extracted with AcOEt, dried over MgSO 4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and crystallized with AcOEt / hexane from obtaining the title compound (11.7 mg, 23% yield) as a pale yellow solid: m.p. 156-158 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.67 (1H, d, J = 8.2 Hz), 7.33-7.50 (5H, m), 7.63-7.83 ( 4H, m), 7.97 (1H, d, J = 4.1 Hz), 8.96 (1H, d, J = 8.0 Hz).

286

Example 73 (Comparative)

3- (3-Phenyl-1-trityl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1150]

<img file="PL2393360T3_D0308.tif" />

[1151] nBuLi (1.6 M solution in hexane, 25 mL, 40 mmol) was added dropwise at -78 ° C to a solution of 4-bromo-3-phenyl-1-trityl-1H-pyrazole (7.96 g, 20.6 mmol) and B (OiPr) 3 (6.92 ml, 30 mmol) in THF (75 ml). After stirring for 1 hour, the reaction mixture was allowed to warm to 0 ° C, quenched with saturated aqueous NH 4 Cl solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (2 / 1-0 / 1) and crystallized from MeOH to give crude (3-phenyl-1-trityl-1H-pyrazol-4-yl) boronic acid (5.73 g) as a white solid.

[1152] A mixture of 3-bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (319 mg, 1.0 mmol), (3-phenyl-1-trityl-1H-pyrazol- acid 4-yl) boronic (645 mg, 1.5 mmol), Pd (PPh3) 4 (58 mg, 0.05 mmol), Na2CO3 (318 mg, 3.0 mmol), DME (7.5 ml) and H2O (1.5 ml) was refluxed overnight under an atmosphere of Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1/1) and crystallized from MeOH to give the title compound (418 mg, 67% yield) as a white solid: m.p. 216-218 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 6.58 (1H, d, J = 7.9 Hz), 7.08 (1H, dd, J = 2.3, 7.9 Hz), 7.23 -7.39 (20H, m), 7.47-7.54 (3H, m), 8.17 (1H, d, J = 7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m / z 625 [M + H]⁺. Anal. calc. for C39H27F3N4O: C, 74.99; H, 4.36; N, 8.97. Found: C, 74.84; H, 4.39; N, 9.01.

Example 74 (Comparative)

3- (3-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

287 [1153]

<img file="PL2393360T3_D0309.tif" />

[1154] A mixture of 3- (3-phenyl-1-trityl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (1.50 g, 2, 4 mmol), TFA (5 mL) and CH2Cl2 (15 mL) were stirred overnight at room temperature. The reaction mixture was basified with 1 M aqueous NaOH and extracted with AcOEt. The extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was recrystallized from MeOH to give the title compound (751 mg, 82% yield) as a white solid: m.p. 206-208 ° C;¹H NMR (300 MHz, DMSO-d6): δ ppm 6.58 (1H, d, J = 7.9 Hz), 7.37-7.67 (9H, m), 8.33 (0.35H, brs), 8.65 (0.65H, brs), 8.91 (1H, d, J = 7.9 Hz), 13.17-17.46 (1H, m). LC-MS (ESI) m / z 383 [M + H] +. Anal. calc. for C20H13F3N4OA35H2O: C, 61.81; H, 3.55; N, 14.42. Found: C, 61.83; H, 3.61; N, 14.49.

Example 75 (Comparative)

3- (1-Methyl-5-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1155]

<img file="PL2393360T3_D0310.tif" />

Example 76 (Comparative)

3- (1-Methyl-3-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) on [1156]

<img file="PL2393360T3_D0311.tif" />

[1157] Suspension 3- (3-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (325 mg, 0.85 mmol), iodomethane (0.081 ml , 1.3 mmol) and K2CO3 (235 mg, 1.7

288 mmol) in DMF (3 mL) was stirred overnight 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 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane / AcOEt to give 3- (1-methyl-5-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine -4 (1H) -one (100 mg, 30% yield) as a white solid: m.p. 193-195 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 3.74 (3H, s), 6.61 (1H, d, J = 7.9 Hz), 6.91 (1H, dd, J = 2.3, 8.3 Hz), 7.25 (1H, s), 7.33-7.40 (3H, m), 7.45-7.52 (4H, m), 8.12 (1H, d, J = 7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m / z 397 [M + H]⁺. Anal. calc. for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.56; H, 3.88; N, 14.09.

[1158] Additional elution and recrystallization from hexane / AcOEt gave 3- (1-methyl-3-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (66 mg, 20% yield) as a white solid: m.p. 181-183 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 4.00 (3H, s), 6.67 (1H, d, J = 7.9 Hz), 7.06 (1H, dd, J = 2.3, 8.3 Hz), 7.357.40 (5H, m), 7.49-7.55 (3H, m), 8.21 (1H, d, J = 7.9 Hz), 8.70 (1H, s). LC-MS (ESI) m / z 397 [M + H]⁺. Anal. Found: C, 63.56; H, 3.85; N, 14.14.

Example 77 (Comparative)

3- [1- (1-Methylethyl) -3-phenyl-1H-pyrazol-4-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1159]

<img file="PL2393360T3_D0312.tif" />

Example 78 (Comparative)

3- [1- (1-Methylethyl) -5-phenyl-1H-pyrazol-4-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1160]

<img file="PL2393360T3_D0313.tif" />

289 [1161] Suspension of 3- (3-phenyl-1H-pyrazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine-4 (1H) -one (325 mg, 0.85 mmol), 2-iodopropane ( 0.130 ml, 1.3 mmol) and K2CO3 (235 mg, 1.7 mmol) in DMF (3 ml) was stirred overnight at 50 ° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and then separated by preparative HPLC to give the title compounds.

[1162] 3- [1- (1-Methylethyl) -3-phenyl-1H-pyrazol-4-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one: white solid ( 27.8 mg, 8% yield, crystallized from hexane / AcOEt); temp.top. 138-140 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 1.60 (6H, d, J = 6.8 Hz), 4.53-4.67 (1H, m), 6.66 (1H, d, J = 7.9 Hz), 7.04 (1H, dd, J = 2.1, 8.1 Hz), 7.34-7.41 (5H, m), 7.49-7.57 (3H, m ), 8.21 (1H, d, J = 7.9 Hz), 8.74 (1H, s). LC-MS (ESI) m / z 425 [M + H]⁺. Anal. calc. for C23H19F3N4O: C, 65.09; H, 4.51; N, 13.20. Found: C, 64.68; H, 4.50; N, 12.98.

[1163] 3- [1- (1-Methylethyl) -5-phenyl-1H-pyrazol-4-yl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one: white solid ( 17.0 mg, 5% yield, recrystallized from hexane / AcOEt); temp.top. 183-186 ° C;¹H NMR (300 MHz, CDCl3): δ ppm 1.45 (6H, d, J = 6.4 Hz), 4.25-4.38 (1H, m), 6.60 (1H, d, J = 7.9 Hz), 6.87 (1H, dd, J = 2.1, 8.1 Hz), 7.25 (1H, s), 7.32-7.38 (3H, m), 7, 45-7.52 (4H, m), 8.11 (1H, d, J = 7.9 Hz), 8.69 (1H, s). LCMS (ESI) m / z 425 [M + H]⁺. Anal. Found: C, 64.95; H, 4.59; N, 13.14.

[1164] Preparative HPLC was carried out under the conditions described below.

Column: YMC CombiPrep Pro C18 RS (50 χ 20 mmI.D. S-5μm, 8 nm)

Column temperature: 25 ° C

Mobile phase: (A) 0.1% TFA in distilled water, (B) 0.1% TFA in acetonitrile Gradient: 0 min (A / B = 64/36)&gt; 1 min (A / B = 64/36) &gt; 30 min (A / B = 64/36)&gt; 30.30 min (A / B = 0/100)&gt; 33.30 min (A / B = 0/100)&gt; 30.60 min (A / B = 64/36)&gt; 35 min (A / B = 64/36)

Flow rate: 25 ml / min

Detector: UV 220 nm

Concentration: 100 mg / ml

Injection volume: 0.150 ml

Retention time: 20.9 min (Example 77) and 24.5 min (Example 78)

290

Example 79 (Comparative)

3- (3-Phenylisoxazol-4-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1165]

<img file="PL2393360T3_D0314.tif" />

[1166] To a solution of 3-ethynyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (104 mg, 0.391 mmol) and N-hydroxybenzenecarboximidoyl chloride (122 mg, 0.782 mmol) in THF (5 ml) Et3N (0.108 ml, 0.782 mmol) was added at 0 ° C. The suspension was stirred at room temperature for 14 hours. The reaction was quenched with water. The mixture was extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and basic silica gel (hexane / AcOEt = 50/50 to 43/57) and crystallized with AcOEt / heptane to give the title compound (82.4 mg, 55% yield) as a white solid: m.p. 217-219 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J = 8.0 Hz), 7.50-7.59 (3H, m), 7.86-7.92 ( 2H, m), 7.94-8.02 (3H, m), 8.15-8.26 (2H, m), 9.09 (1H, d, J = 8.2 Hz). Anal. calc. for C20H12F3N3O2: C, 62.67; H, 3.16; N, 10.96. Found: C, 62.60; H, 3.19; N, 10.95.

Example 80 (Comparative)

3- (4-Phenyl-1,3-oxazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1167]

<img file="PL2393360T3_D0315.tif" />

[1168] To a solution of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbaldehyde (52.8 mg, 0.197 mmol) in MeCN (0.4 mL) was added N-methylidene-1 - [(4-methylphenyl) sulfonyl] -1-phenylmethanamine (53.8 mg, 0.197 mmol) and K2CO3 (35.4 mg, 0.256 mmol) at room temperature. The suspension was stirred at room temperature for 1 day. The suspension was diluted with water, extracted with AcOEt, washed with brine, dried over MgSO4, filtered, concentrated in vacuo, purified by silica gel column chromatography

291 (hexane / AcOEt = 90/10 to 0/100) and crystallized with AcOEt / hexane to obtain the title compound (18.6 mg, 25% yield) as a solid: ¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.75 (1H, d, J = 8.5 Hz), 7.33-7.43 (3H, m), 7.647.70 (2H, m) , 7.72-7.83 (2H, m), 7.92-8.01 (2H, m), 8.65 (1H, s), 9.02 (1H, d, J = 7.7 Hz ). Anal. calc. for C20H12F3N3O2OBH2O: C, 62.08; H, 3.23; N, 10.86. Found: C, 62.08; H, 3.38; N, 10.67.

Example 81 (Comparative)

3- (2-Phenyl-1H-imidazol-1-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one [1169]

<img file="PL2393360T3_D0316.tif" />

[1170] A solution of 3-amino-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (200 mg, 0.783 mmol) and glyoxal (40% solution, 0.0895 mL, 0.783 mmol) in MeOH (2 ml) was stirred at room temperature for 20 hours. Benzaldehyde (0.159 ml, 1.57 mmol) and NH4Cl (84 mg, 1.57 mmol) were added to the solution. The mixture was heated to reflux for 90 minutes. H3PO4 (0.106 mL) was added to the mixture. The mixture was heated to reflux for 24 hours. The mixture was diluted with water, extracted with AcOEt, washed with aqueous NaHCO3, dried over Na2SO4, filtered, concentrated in vacuo, purified by silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and on basic silica gel (hexane / AcOEt = 50/50 to 0/100) and recrystallized from AcOEt / heptane to give the title compound (9.3 mg, 3% yield) as a white solid: m.p. 204-205 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 6.82 (1H, d, J = 8.0 Hz), 7.20 (1H, d, J = 1.6 Hz), 7.33-7 , 41 (3H, m), 7.44-7.50 (2H, m), 7.62 (1H, s), 7.64-7.81 (4H, m), 9.06 (1H, d , J = 8.0 Hz). Anal. calc. for C20H13F3N4O: C, 62.83; H, 3.43; N, 14.65. Found: C, 62.50; H, 3.64; N, 14.56.

Example 82

5-Methoxy-3- (2-phenyl-1H-imidazol-1-yl) -1- [3- (trifluoromethyl) phenyl] pyridazine 4 (1H) -one [1171]

292

<img file="PL2393360T3_D0317.tif" />

[1172] A solution of 3-amino-5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (300 mg, 1.05 mmol) and glyoxal (40% solution, 0.240 ml, 2 , 10 mmol) in MeOH (3 mL) was stirred at room temperature for 24 hours. Benzaldehyde (0.428 mL, 4.21 mmol) and NH4Cl (225 mg, 4.21 mmol) were added to the solution. The mixture was heated to reflux for 2 hours. H3PO4 (0.142 mL) was added to the mixture. The mixture was heated to reflux for 20 hours. The mixture was diluted with water and saturated aqueous NaHCO3, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and by HPLC and recrystallized from AcOEt / hexane to give the title compound (126 mg, 29% yield) as a white solid: m.p. 167-170 ° C.¹H NMR (DMSO-d6, 300 MHz): δ ppm 3.94 (3H, s), 7.19 (1H, d, J = 1.5 Hz), 7.31-7.49 (5H, m) , 7.61 (1H, d, J = 1.5 Hz), 7.68-7.91 (4H, m), 8.80 (1H, s). Anal. calc. for C21H15F3N4O2-0.7 ^: C, 59.35; H, 3.89; N, 13.18. Found: C, 59.28; H, 3.69; N, 13.12.

[1173] Preparative HPLC was carried out under the conditions described below.

Column: Waters SunFire Column C18 (30 χ 50 mm S-5μm)

Column temperature: 25 ° C

Mobile phase: (A) 0.1% TFA in distilled water, (B) 0.1% TFA in acetonitrile Gradient: 0 min (A / B = 90/10) 1.20 min (A / B = 90/10 ) 4.75 min (A / B = 0/100)

7.75 min (A / B = 0/100) 7.85 min (A / B = 90/10) 8.50 min (A / B = 90/10)

Flow rate: 70 ml / min