Pyridazinone compounds

Phosphodiesterases (PDEs) are a superfamily of enzymes encoded by the 21st gene, and are divided into several different families, according to structural and functional properties. These enzymes metabolically inactivate unavoidable intracellular secondary messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); These PDEs selectively catalyze the hydrolysis of the 3'-ester bond, forming inactive 5-monophosphate. Based on substrate specificity, PDE families can be classified into three other groups: i) cAMP-PDEs (PDE4, PDE7, PDE8), ii) cGMP-PDEs (PDE5, PDE6 and PDE9) and iii) dual substrate PDEs (PDE1, PDE2). , PDE3, PDE10 and PDE11).

These cAMPs and cGMPs are involved in the regulation of virtually every physiological process, such as the creation and action of a pro-inflammatory mediator, ion channel function, muscle relaxation, memory learning and formation, differentiation, apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis. Especially in neurons, these secondary messengers play a significant role in regulating synaptic transmissions, and

54504 Β1 also in neuronal differentiation and survival (Nat. Rev. Drug Discov. 2006, vol. 5: 660-670). Regulation of these processes by cAMP and cGMP is accompanied by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a number of substrates, including transcription factors, ion channels, and receptors that regulate a number of physiological processes. Concentrations of intracellular cAMPs and cGMPs appear to be occasionally, spatially and functionally divided into categories via adenyl and guanyl cyclases, in response to extracellular signaling and their degradation by PDEs (Circ. Res. 2007, vol. 100 (7): 950-966) . Furthermore, PDEs provide the only mode of degradation of cyclic nucleotides cAMP and cGMP in cells, and therefore PDEs play an essential role in cyclic nucleotide signaling. Therefore, PDEs may represent promising targets for drugs in a variety of therapies.

Phosphodiesterase 10A (PDE10A) was independently detected in 1999 by three groups (Proc. Natl. Acad. Sci. USA 1999, vol. 96: 8991-8996, J. Biol. Chem. 1999, vol. 274: 1843818445, Gene 1999, vol. 234: 109-117). Expression studies have shown that PDE10A has the most limited distribution within all known PDE families; PDE10A mRNA is abundantly 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 PDE10A protein are significantly enriched in the medium of spinal neurons (MSNs) of the striatum (Eur. J. Biochem. 1999, vol. 266: 1118-1127, Brain Res. 2003, vol. 985: 113-126). These MSNs are classified into two groups: MSN, which expresses the D1 dopamine receptors, which are responsible for the direct (striatonigral) pathway, and MSN, which expresses the D2 dopamine receptors, which are responsible for the indirect (striatopalidal) pathway. The function of the direct pathway is planning and execution, while the function of the indirect pathway is to act as a brake on behavioral activation. Since PDE10A is expressed in both MSNs, PDE10A inhibitors can activate both of these pathways. The antipsychotic efficacy of existing medications, D2 or D2 / 5-HT2A antagonists, mainly stems from their activation of the indirect pathway in the striatum. Since PDE10A inhibitors are able to activate this pathway, this suggests that PDE10A inhibitors represent promising antipsychotic drugs. Excess D2 receptor antagonism in the brain, via D2 antagonists, causes problems through extrapyramidal side effects and hypeprolactinemia. However, PDE10A expression is limited to these stratial pathways in the brain, and therefore side effects, induced by PDE10A inhibitors, are expected to be weaker compared to existing D2 antagonists. In terms of hyperprolactinaemia,

54504 Β1 PDE10A inhibitors would not cause an increase in prolactin, due to the lack of antagonism to the D2 receptor in the pituitary gland. In addition, due to the presence of PDE10A in the direct pathway, it is likely that inhibition of PDE10A will have a certain advantage over existing D2 antagonists; it is believed that the direct pathway promotes the desired action, and that activation of this pathway by PDE10A inhibitors may counteract the extrapyramidal symptoms caused by excess D2 receptor antagonism. In addition, activation of this pathway can facilitate stratial-thalamic outflow while promoting the execution of procedural strategies. In addition, increasing secondary messenger levels, without blocking dopamine receptors and / or other neurotransmitters, may also provide therapeutic benefits with fewer adverse side effects, compared to existing antipsychotics (e.g., hyperprolactinaemia and weight gain). This unique distribution and function in the brain suggests that PDE10A represents an important, new goal in the treatment of neurological and psychiatric disorders, and especially psychotic disorders, such as schizophrenia.

Phosphodiesterase (PDE) 10 inhibitor is a compound represented by the formula:

[NETP where Z

Which is described in document WO 2006/072828.

Furthermore, a compound represented by the general formula has been shown to be a phosphodiesterase (PDE) 10 inhibitor.

54504 Β1

<img file="RS54504B1_D0001.tif" />

<img file="RS54504B1_D0002.tif" />

which is also described in document WO 2008/001182.

In addition, US 2008/207902 describes pyrazolopyridin-4-yl pyridazinone derivatives as phosphodiesterase inhibitors.

DISCLOSURE OF THE ESSENCE OF THE INVENTION

TECHNICAL PROBLEM

Further development of new phosphodiesterase (PDE) 10A inhibitors is required.

PROBLEM SOLUTION

These inventors have discovered that the compound represented by formula (lo), or a salt thereof (to be referred to in this application as compound (lo)) has an inhibitory effect on PDE 10A, and after extensive testing have completed this invention.

Among these compounds (lo), the compound represented by formula (I), or a salt thereof (hereinafter referred to as compound (I)), represents a new compound.

In this application, compound (s), including compound (I), will also be referred to as a compound of the present invention.

Namely, the following features represent the present invention.

[1] Compound of formula (I)

54504 Β1

<img file="RS54504B1_D0003.tif" />

where are they

R¹ represents a substituent,

R² represents a substituent,

R³ represents a hydrogen atom, or a substituent,

Ring A represents an aromatic ring which may be substituted, and Ring B represents a 5-membered heteroaromatic ring which may be substituted;

where the substituent for R¹, R² or R³, represent substituents, such as an aromatic ring which may be substituted for Ring A, or substituents such as a 5-membered heteroaromatic ring which may be substituted for Ring B, or are selected from the group of substituents A;

[Substituent group A] (1) a halogen atom;

(2) some nitro group;

(3) some cyano group;

(4) a carboxy group, which can be esterified;

(5) a C1-10 alkyl group, 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 C 3-7 cycloalkyl group, which may be substituted;

(9) an Sb-14 aryl group, which may be substituted;

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

(11) an Sb-14 aryl-C2-6 alkenyl group, which may be substituted;

(12) a heterocyclic group, which may be substituted;

(13) a hydroxy group;

(14) a C 1-10 alkoxy group, which may be substituted;

54504 Β1 (15) a C3-7 cycloalkoxy group, which may be substituted;

(16) a C1-4 aryloxy group, which may be substituted;

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

(18) a C1-10 alkyl-carbonyloxy group, which may be substituted;

(19) a C1-10 alkoxy-carbonyloxy group, which may be substituted;

(20) a mono-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(21) a di-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(22) a C 1-6 aryl-carbonyloxy group, which may be substituted;

(23) baking a mono- or di-Ce-aryl-carbamoyloxy group, which may be substituted;

(24) a heterocyclic-oxy ​​group, which may be substituted;

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

(26) peka mercapto group;

(27) a C1-10 alkylsulfinyl group, which may be substituted;

(28) a C 3-7 cycloalkylsulfanyl group, which may be substituted;

(29) a C6-arylsulfinyl group, which may be substituted;

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

(31) a heterocyclic-sulfanyl group, which may be substituted;

(32) a formyl group;

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

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

(35) a C 1-6 arylcarbonyl group, which may be substituted;

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

(37) a heterocyclic-carbonyl group, which may be substituted;

(38) a C1-10 alkylsulfonyl group, which may be substituted;

(39) a C 3-7 cycloalkylsulfonyl group, which may be substituted;

(40) a C 1-6 arylsulfinyl group, which may be substituted;

(41) a heterocyclic-sulfonyl group, which may be substituted;

(42) a C1-10 alkylsulfinyl group, which may be substituted;

(43) a C 3-7 cycloalkylsulfinyl group, which may be substituted;

(44) a C 1-6 arylsulfinyl group, which may be substituted;

(45) a heterocyclic-sulfinyl group, which may be substituted;

(46) a sulfo group;

(47) a sulfamoyl group;

54504 Β1 (48) peca sulfinamoyl group;

(49) a sulfenamoyl group;

(50) a thiocarbamoyl group;

(51) a carbamoyl group, which may be substituted;

(52) an amino, mono- or di-C1-10 alkylamino group, which may be substituted, a mono- or sL-S2-7 cycloalkylamino group, which may be substituted, mono-yl; a substituted di-Sb- and arylamino group, a substituted mono- or di-C7- or aralkylamino group, a substituted heterocyclic amino group, a substituted Sb-14 aryl-carbonylamino group , formylamino,

C1-10 alkyl-carbonylamino group, which may be substituted, Sz-7 cycloalkyl-carbonylamino group, which may be substituted, heterocyclic-carbonylamino group, which may be substituted, Sz-7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic -oxycarbonylamino group, which may be substituted, carbamoylamino group, which may be substituted,

A C1-10 alkylsulfonylamino group, which may be substituted,

S3-7 substituted cycloalkyl-sulfonylamino group, optionally substituted heterocyclic sulfonylamino group, optionally substituted Sb-14 arylsulfonylamino group, and among the above-mentioned Substituent Group A, “Smo is an alkoxycarbonyl group, which may be substituted. be substituted, a "C1-10 alkyl group, which may be substituted," a C1-6 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 "C 1-10 alkyl-carbonyloxy group which may be substituted," a C 1-10 alkoxy-carbonyloxy group which may be substituted, a "mono-C 1-10 alkyl-carbamoyloxy group which may be substituted," a di-C 1-10 alkylcarbamoyloxy group, which may be substituted, a C 1-10 alkylsulfanyl group, which may be substituted, a C 1-10 alkylcarbonyl group, which may be substituted,

54504 Β1 ”C 1 -C 6 alkylsulfonyl group, which may be substituted,” We are an alkylsulfinyl group, which may be substituted, “C 1-6 alkyl-carbamoyl group, which may be substituted,” mono- or di-C 1-10 alkylamino group, which may be substituted, a "substituted" C1-8 alkyl-carbonylamino group, "a mono- (C1-10-alkyl-carbonyl) -amino group, which may be substituted,

A C1-10 alkoxycarbonylamino group, which may be substituted, and a C1-10 alkylsulfonylamino group, which may be substituted, and their substituents may be selected from the following group of substituents B, the number of substituents ranging from 1 to a maximum number of may be substituted, more preferably from 1 to 3, [Substituent group B] (a) a halogen atom;

(b) a hydroxy group;

(c) a nitro group;

(d) a cyano group;

(e) an Sb-14 aryl group, which may be substituted;

(f) a C1-14 allyloxy 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 having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group, which may be substituted;

(j) C3-7 cycloalkyl;

(k) a substituted C 1-4 alkoxy;

(l) some formyl;

(m) some C1-10 alkylcarbonyl;

(n) a C3-7 cycloalkylcarbonyl;

(o) an Ce-14 aryl-carbonyl;

(p) some C7-16 aralkylcarbonyl;

(q) a C1-10 alkoxycarbonyl;

(g) an Ce-14 aryloxycarbonyl;

54504 Β1 (s) some C7-16 aralkyloxycarbonyl;

(t) some C1-10 alkylsulfanyl;

(u) some C1-10 alkylsulfinyl;

(v) some C1-10 alksulfonyl;

(w) a carbamoyl group;

(x) some thiocarbamoyl;

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

(z) a di-C 1-6 alkylcarbamoyl;

(aa) a mono- or di-C 6 -alkylcarbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic-carbamoyl, having 1 to 4 heteroatoms, selected from nitrogen, sulfur and oxygen, and among the above-mentioned Substituent Group A, "Se-14 aryloxy" -substituted, which may be substituted, "C2-6 aralkyloxy-carbonyl, which may be substituted," Sz-7 cycloalkyl - C2-6 alkynyl, which may be substituted, "Sz-7 cycloalkyl, which may be substituted," Se -14 aryl, which may be substituted, "07-16 aralkyl, which may be substituted,

Sb-14 substituted aryl-C2-6 alkenyl, substituted heterocyclic group, substituted Sz-7 cycloalkyloxy,

Sb-14 aryloxy, which may be substituted, "07-16 aralkyloxy, which may be substituted," C5-14 aryl-carbonyloxy, which may be substituted, rnono- or di-C6-aryl-carbamoyloxy, which may be substituted , optionally substituted heterocyclic-oxy, optionally substituted aromatic heterocyclic-oxy,

C3-7 cycloalkylsulfanyl, which may be substituted, "Sb-14 arylsulfanyl, which may be substituted," 07-16 aralkylsulfanyl, which may be substituted, heterocyclic-sulfanyl, which may be substituted,

C3-7 cycloalkyl-carbonyl, which may be substituted, "Sb-14 aryl-carbonyl, which may be substituted,

Ό7-16 aralkyl-carbonyl, which may be substituted,

54504 Β1 substituted heterocyclic-carbonyl, "Sz-7 cycloalkylsulfonyl, which may be substituted," C1-14 arylsulfonyl, which may be substituted, heterocyclic-sulfonyl, which may be substituted, "Sz-7 cycloalkylsulfinyl, which may be substituted. substituted, "C1-14 arylsulfinyl, which may be substituted, heterocyclic-sulfinyl, which may be substituted," carbamoyl group, which may be substituted, amino group, which may be substituted, "Substituted mono- or sN-S2-7 cycloalkylamino group," Substituted mono- or di-C1-C14-arylamino group, "Substituted mono- or di-C7-aralkylamino group , A substituted heterocyclic amino group, a substituted Se-14 arylcarbonylamino group, a substituted C3-7 cycloalkylcarbonylamino substituted group, a substituted heterocycliccarbonylamino group, "Sz-7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic-oxycarbonylamino group, which may be substituted, carbamoylamino group, which may be substituted, alkylsulfonylamino group, which may be substituted," Sz-7 cycloalkylo-sulfonyla may be substituted, a heterocyclic sulfonylamino group, which may be substituted, and a "Sv-14 arylsulfonylamino group, which may be substituted, whose substituents may be selected from the above-mentioned Substituent Group B and the following substituent from the group of co-substituents B ', and the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents:

[Substituent group B '] (a) C 1-10 alkyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 5 - 14 arylamino, mono- or di-C7-6 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-6 arylcarbonyl, C7-16 aralkylcarbonyl , C1-10 alkoxycarbonyl, C1-6 aryloxycarbonyl, C7-16

54504 Β1 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-arylcarbamoyl;

(b) C2-6 alkenyl, 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-arylamino, mono - or di-C7-aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1 .10 alkoxycarbonyl, C1-6 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C8-aryl-carbamoyl; and (c) C2-6 alkynyl, which may be substituted by one or more substituents selected from halogen atoms, hydroxy, cyano, amino, mono- or di-C1-C10 alkylamino, mono- or di-C6-arylamino , mono- or di-C7-aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-6 arylcarbonyl, C7-16 aralkylcarbonyl , C1-10 alkoxycarbonyl, C1-10 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-aryl-carbamoyl groups;

or some of their salts.

[2] A compound of the above [1], wherein R² represents a halogen atom, a hydroxy group, a C1-10 alkyl group which may be substituted, or a C1-10 alkoxy group which may be substituted.

[3] A compound of the above [2], wherein R² represents 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] A compound of the above [2], wherein R² represents a C1-10 alkoxy group.

[5] A compound of the above [2], wherein R¹ represents a phenyl group, which may be substituted with 1 to 5 substituents selected from atoms of a halogen, peka

54504 Β1

C1-10 alkyl groups, which may be substituted, and some C1-10 alkoxy groups, which may be substituted.

[6] A compound of the above [2], wherein R¹ represents a phenyl group, which may be substituted with 1 to 5 substituents selected from a halogen atom, a C 1-10 alkyl group and a C 1-10 alkoxy group.

[7] A compound of the above [2], wherein R¹ represents a phenyl group, which may be substituted by 1 to 5 halogen atoms.

[8] A compound of the above [2], wherein R³ represents a hydrogen atom, or a C1-10 alkoxy group, which may be substituted.

[9] A compound of the above [2], wherein R³ represents a hydrogen atom, or a C1-10 alkoxy group.

[10] A compound of the above [2], wherein R³ represents a hydrogen atom.

[11] The compound of the above [2], wherein Ring A represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-10 alkyl group, which may bitisubstituted, (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 up to 3 nitrogen atoms as heteroatoms, which may be substituted, (5) a 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) a C 3-7 cycloalkyl-C 2-6 alkynyl group, which may be substituted, (11) a tetrahydropyranyl group, which may be substituted, (12) a dihydropyranyl group, which may be substituted, (13) ) a mono- (C1-10 alkylcarbonyl) -amino group, which can be

54504 Β1 substituted, (14) an optionally substituted S-mo alkoxycarbonyl group, (15) an optionally substituted C1-10 alkylsulfinyl group, and (16) an optionally substituted S-mo alkylsulfanyl group .

[12] The compound of the above-mentioned [2], wherein Ring A represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-4 alkyl group, which may be substituted, (3) an C 1-10 alkoxy group, which may be substituted, (4) a S 2-7 cycloalkyl group, (5) a halogen C 1-10 alkylsulfonyloxy group, (6) a C 3-7 cycloalkyl-C 1-6 alkynyl group, and (7) a 4- to 6-membered heterocyclic group, containing 0 or 1 oxygen atom and up to 3 nitrogen atoms as heteroatoms, which may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, a pexo oxo group, a C1-10 alkoxycarbonyl group , some

C1-10 alkoxy groups which may be substituted and C1-10 alkyl groups which may be substituted.

[13] The compound of the above [2], wherein Ring A represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-10 alkyl group, which may be substituted by 1 to 3 halogen atoms, (3) a C 1-10 alkoxy group, which may be substituted by 1 to 3 halogen atoms, (4) a C 3-7 cycloalkyl group, (5) a halogenated C 5-10 alkylsulfonyloxy group, ( 6) some C3-7 cycloalkyl - C2-6 alkenyl group, and (7) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and up to 3 nitrogen atoms as heteroatoms, which may be substituted by 1 to 4 substituents selected from halogen atoms, some hydroxy groups, some oxo groups, some C1-10 alkoxy-carbonyl groups, some C1-10 alkoxy

54504 Β1 groups, which may be substituted by halogen and some C1-4 alkyl groups, which may be substituted by halogen.

[14] The compound of the above [2], wherein Ring A represents a benzene ring substituted with (1) (i) 1 or 2 halogen atoms, or (ii) one C 1-10 alkoxy group, and (2) one 4 - up to a 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which may be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxy group, an oxo group, some C 1-4 alkoxycarbonyl groups, some C 1-10 alkoxy groups, which may be substituted by halogen and some C1-10 alkyl groups, which may be substituted by halogen.

[15] The compound of the above-mentioned [14], wherein this 4- to 6-membered heterocyclic group, containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as a heteroatom, represents a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a pyrazoyl group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

[16] The compound of the above-mentioned [2], wherein Ring B represents an imidazole ring, a pyrazole ring, a triazole ring or a tetrazole ring, each of which may be further substituted with 1 to 3 substituents selected from atoms of a halogen and some C 1-4 alkyl group which may be substituted by halogen.

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

[18] A compound of the above [2], wherein Ring B represents a pyrazole ring.

[19] A compound of the above [2], where R¹ represents a phenyl group, which may be substituted with 1 to 5 substituents selected from halogen atoms, a C1-10 alkyl group which may be substituted and some C 1-4 alkoxy

54504 Β1 group which may be substituted, R² represents a halogen atom, a hydroxy group, a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted, R³ represents a hydrogen atom, or a C1-10 alkoxy group, which may be substituted, Ring A represents 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, which may be substituted, (5) a 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) a C3-7 cycloalkyl-C2-6 alkynyl group, which may be substituted, (11) a tetrahydropyranyl group, which may be substituted, (12) a dihydropyranyl group, which may be substituted, (13) a mono- (C1-10 alkyl-carbonyl) -amino group, which may be substituted, (14) a C1-10 alkoxy-carbonyl 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, and

Ring B represents an imidazole ring, a pyrazole ring, a triazole ring or a tetrazole ring, each of which may be substituted with 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group, which may be substituted. with halogen.

[20] The compound of the above-mentioned [19], wherein Ring A represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-10 alkyl group, which may be substituted, (3) a C1-10 alkoxy group, which may be substituted, (4) a C3-7 cycloalkyl group,

54504 Β1 (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 may be substituted by one or more substituents selected from halogen atoms, a hydroxy group, an oxo group, a C1-10 alkoxycarbonyl group, some C1-10 alkoxy groups which may be substituted and some C1-10 alkyl groups which may be substituted.

[21] A compound of the above [2], wherein R¹ represents 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 represents 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, R³ represents a hydrogen atom, iii a C1-10 alkoxy group, Ring A represents a benzene ring, which may be substituted with 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 halogenated C1-10 alkylsulfonyloxy group. 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 may be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxy group , some oxo groups, drug C1-10 alkoxy-carbonyl groups, some C1-10 alkoxy groups which may be substituted by halogen and some C1-10 alkyl groups which may be substituted by halogen,

Ring B represents a pyrazole ring which may be further substituted with 1 to 3 substituents selected from a halogen atom and a C1-10 alkyl group which may be substituted by halogen.

54504 Β1 [22] A compound of the above [2], where R¹ represents a phenyl group, which may be substituted by 1 to 5 halogen atoms, R² represents a C1-10 alkoxy group, R3 represents a hydrogen atom, Ring A represents a benzene ring substituted by (1) (i) 1 or 2 halogen atoms, or (ii) one S-mo alkoxy group, and (2) 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 by 1 to 4 substituents selected from a halogen atom, a hydroxy group, an oxo atom groups, some S-mo alkoxy-carbonyl groups, some C1-10 alkoxy groups, which may be substituted by halogen, and light C1-10 alkyl groups, which may be substituted by halogen,

Ring B represents a pyrazole ring.

[23] The compound of the above-mentioned [22], wherein this 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, represents a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a a pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

[24] A compound of the above [1], wherein R¹ represents an aromatic group, which may be substituted, Ring A represents an aromatic ring, which is substituted by (a) one substituent selected from (1) a Sz-7 cycloalkyl group which may be substituted, and (2) some 4 - up to a 6-membered heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms, which may be substituted, and (b) one or more other substituents.

[25] A compound of the above [24], wherein R¹ represents a phenyl group, which may be substituted, R² represents a halogen atom, a hydroxy group, a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted, R³ represents a hydrogen atom, iii a C1-10 alkoxy group, which

54504 Β1 may be substituted, Ring A represents a benzene ring, which is substituted with one substituent, selected from (1) a C3-7 cycloalkyl group, which may be substituted, (2) a dihydropyranyl group, which may be substituted, (3) an optionally substituted tetrahydropyranyl group, and (4) a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms which may be substituted, and may be further substituted with other substituents, and

Ring B represents an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an isoxazole ring, a 1,3-oxazole ring, a furan ring, or a thiophene ring, each of which may be substituted.

[26] The compound of the above-mentioned [25], wherein this 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, represents a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a a pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group, an imidazolidinyl group, an isoxazolyl group, a pyridyl group, some piperazinyl group or some thiazolyl group.

[27] The compound of the above-mentioned [24], wherein the additional substituents represent 1 to 4 substituents selected from (1) a halogen atom, (2) an oxo group, (3) a hydroxy group, (4) an S1-10 an 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-yl sulfonyl group, (8) a cyano group, (9) a carbamoyl group, (10) a halogenated C 1-10 alkylsulfonyloxy group, (11) an S 2-7 cycloalkyl-C 1-6 alkynyl group, (12) a di-C 1-10 alkyl-amino group, (13) a mono- (C 1-6 alkylcarbonyl) -amino group,

54504 Β1 (14) some C1-10 alkoxycarbonyl group, (15) some phenoxy group, (16) some C1-10 alkylsulfinyl group, (17) some benzimidazol-2-yloxy group, ί (18) some benzimidazole-2- the sulfonyl group.

[28] A compound of the above [24], wherein R¹ represents a phenyl group, which may be substituted by 1 to 5 halogen atoms, R² represents a 01-10 alkoxy group, R³ represents a hydrogen atom, Ring A represents 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 may be substituted by 1 to 4 a substituent selected from a halogen atom, a hydroxy group, an oxo group, a halogenated G1-10 alkoxy group, We have an alkoxycarbonyl group and a halogen-substituted C1-10 alkyl group which may be further substituted by 1 or 2 substituents selected from a halogen atom and a C1-10 alkoxy group and Ring B represents a pyrazole ring.

[29] The compound of the above-mentioned [28], wherein this 4- to 6-membered heterocyclic group, containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, represents a morpholino group, a pyrrolyl group, a dihydropyrolyl group, let the pyrazoles! a group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

[30] The compound of the above [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 of the above-mentioned [1], which is 1- [2-fluoro-4- (2-oxopyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5- or) pyridazin4 (1H) -one, or a salt thereof.

54504 Β1 [32] The compound of the above-mentioned [1], which is 1- [4- (3,4-difluoro-1H-pyrrol-1-yl) 2-fluorophenyl] -5-methoxy- (1-phenyl-1H-pyrazole) -5-yl) pyridazin-4 (1H) -one, or a salt thereof.

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

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

[35] The compound of 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) pyridazin-4 (1H) -one, or a salt thereof.

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

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

[38] The compound of the above [1], which is 1- [4- (4,4-dimethyl-2-oxopyrrolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazole) -5-yl) pyridazin-4 (1H) -one, or a salt thereof.

[39] The compound of 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 of the above [1], which is 5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one, or a salt thereof.

[41] A medicament comprising a compound of the above-mentioned [1] to [40], [42] a medicament of the above-mentioned [41] for the use of phosphodiesterase 10A inhibition.

54504 Β1 [43] A medicament of the above [41] for use in the prevention or treatment of schizophrenia, autism, Alzheimer's disease, bipolar disorder, Parkinson's disease, Huntington's disease, obesity, drug dependence or attention deficit / hyperactivity disorder.

[44] Use of a compound of formula (lo):

where

R¹ represents a substituent,

R² represents a substituent,

R³ represents a hydrogen atom, or a substituent,

Ring A represents an aromatic ring which may be substituted, and Ring B represents a 5-membered heteroaromatic ring, which may be substituted, wherein the substituent for R¹, R² or R³, chooses between substituents of an aromatic ring which may be substituted for Ring A, or substituents of a 5-membered heteroaromatic ring which may be substituted for Ring B, from the Group of substituents A;

[Substituent group A] (1) a halogen atom;

(2) some nitro group;

(3) some cyano group;

(4) a carboxy group, which can be esterified;

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

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

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

54504 Β1 (8) a C3-7 cycloalkyl group, which may be substituted;

(9) a Ce-14 aryl group, which may be substituted;

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

(11) a C 1-6 aryl-C 2-6 alkenyl group, which may be substituted;

(12) a heterocyclic group, which may be substituted;

(13) a hydroxy group;

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

(15) a C 3-7 cycloalkoxy group, which may be substituted;

(16) a C 1-6 aryloxy group, which may be substituted;

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

(18) a C1-10 alkyl-carbonyloxy group, which may be substituted;

(19) a C1-10 alkoxy-carbonyloxy group, which may be substituted;

(20) a mono-C 5 alkyl-carbamoyloxy group, which may be substituted;

(21) a di-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(22) a C 1-6 aryl-carbonyloxy group, which may be substituted;

(23) a mono- or di-C6-aryl-carbamoyloxy group, which may be substituted;

(24) a heterocyclic-oxy ​​group, which may be substituted;

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

(26) peka mercapto group;

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

(28) a C 3-7 cycloalkylsulfanyl group, which may be substituted;

(29) a C6-arylsulfanyl group, which may be substituted;

(30) a C7-1S aralkylsulfanyl group, which may be substituted;

(31) a heterocyclic-sulfanyl group which may be substituted;

(32) a formyl group;

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

(34) a C 3-7 cycloalkylcarbonyl group, which may be substituted;

(35) a C 1-6 arylcarbonyl group, which may be substituted;

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

(37) a heterocyclic-carbonyl group, which may be substituted;

(38) a C1-10 alkylsulfonyl group, which may be substituted;

(39) a C 3-7 cycloalkylsulfonyl group, which may be substituted;

(40) baking a Ce-u arylsulfonif group, which may be substituted;

54504 Β1 (41) a heterocyclic-sulfonyl group which may be substituted;

(42) a C1-10 alkylsulfinyl group which may be substituted;

(43) a C 3-7 cycloalkylsulfinyl group, which may be substituted;

(44) a C 1-6 arylsulfinyl group, which may be substituted;

(45) a heterocyclic-sulfinyl group, which may be substituted;

(46) a sulfo group;

(47) a sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) a thiocarbamoyl group;

(51) a carbamoyl group, which may be substituted;

(52) an amino, mono- or di- C 1-4 alkylamino group, which may be substituted, a mono- or sN-S 2-7 cycloalkylamino group, which may be substituted, a mono- or di-C 6 arylamino group, which may be a substituted, mono- or di-C7-ie aralkylamino group, which may be substituted, a heterocyclic amino group, which may be substituted, a C1-14 aryl-carbonylamino group, which may be substituted, formylamino,

C1-10 alkyl-carbonylamino group, which may be substituted, Sz-7 cycloalkyl-carbonylamino group, which may be substituted, heterocyclic-carbonylamino group, which may be substituted, Sz-7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic -oxycarbonylamino group, which may be substituted, carbamoylamino group, which may be substituted,

A C1-10 alkylsulfonylamino group, which may be substituted,

S3-7 substituted cycloalkyl-sulfonylamino group, which may be substituted, heterocyclic sulfonylamino group, which may be substituted; be substituted, a 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,

54504 Β1

C 1-10 alkoxy group, which may be substituted, "C 1-10 alkyl-carbonyloxy group, which may be substituted," C 1-10 alkoxy-carbonyloxy group, which may be substituted, "mono-C 1-10 alkyl-carbamoyloxy group , which may be substituted, ”a di-C 1-10 alkyl-carbamoyloxy group, which may be substituted,

C1-10 alkylsulfinyl group, which may be substituted, "C1-10 alkylsarbonyl group, which may be substituted," We are an alkylsulfonyl group, which may be substituted, "C1-10 alkylsulfinyl, group, which may be substituted," C1-10 alkyl-carbamoyl group, which may be substituted, "mono- or di-C 1-6 alkylamino group, which may be substituted," C 1-10 alkyl-carbonylamino group, which may be substituted, "mono- (C 1-10 alkyl- carbonyl) -amino group, which may be substituted, A C1-10 alkoxycarbonylamino group, which may be substituted, and a C1-10 alkylsulfonylamino group, which may be substituted,

Their substituents can be selected from the following Substituent Group B, and the number of substituents ranges from 1 to a maximum number, which may be substituted, more preferably from 1 to 3, [Substituent Group B] (a) a halogen atom;

(b) baking hydroxy group;

(c) a nitro group;

(d) a cyano group;

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

(f) a Ce-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 having 1 to 4 heteroatoms, selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group, which may be substituted;

(j) C3-7 cycloalkyl;

54504 Β1 (k) some C 1-4 alkoxy, which may be substituted;

(l) some formyl;

(m) some C1-10 alkylcarbonyl;

(n) a C3-7 cycloalkylcarbonyl;

(o) an Ce-14 aryl-carbonyl;

(p) some C7-16 aralkylcarbonyl;

(q) a C 1-10 alkoxycarbonyl;

(g) an Sb- and aryloxy-carbonyl;

(s) a C7-16 aralkyloxycarbonyl;

(t) some C1-10 alkylsulfanyl;

(u) some C1-10 alkylsulfinyl;

(v) a C1-10 alkylsulfonyl;

(w) a carbamoyl group;

(x) some thiocarbamoyl;

(y) a mono- C1-10 alkylcarbamoyl;

(z) some di-C 1-6 alkylcarbamoyl;

(aa) some mono- or di-Ce-u aryl-carbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic-carbamoyl having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and among the above-mentioned Substituent Group A are, "Cs-i4 aryloxy-carbonyl, which may be substituted, ”C7-16 aralkyloxy-carbonyl, which may be substituted,

C3-7 cycloalkyl - C2-6 alkynyl, which may be substituted, "S2-7 cycloalkyl, which may be substituted," Sb- and aryl, which may be substituted,

C7-16 aralkyl, which may be substituted, "C5-14 aryl-C2-e alkenyl, which may be substituted," heterocyclic group, which may be substituted, "C3-7 cycloalkyloxy, which may be substituted," Sb-i aryloxy, which may be substituted, "C1-16 aralkyloxy, which may be substituted," C1-14 aryl-carbonyloxy, which may be substituted, mono- or di-C6-aaryl-carbamoyloxy, which may be substituted,

54504 Β1 substituted heterocyclic-oxy, aromatic substituted heterocyclic-oxy, "Sz-7 cycloalkylsulfanyl, which may be substituted," C5-14 arylsulfanyl, which may be substituted, "C7-16 aralkylsulfanyl, which may be substituted , optionally substituted heterocyclicsulfanyl, "Sz-7 substituted cycloalkylcarbonyl," substituted Sb-14 arylcarbonyl, substituted S7-16 aralkylcarbonyl, "Heterocyclic-carbonyl, which may be substituted," Sz-7 cycloalkylsulfonyl, which may be substituted, "Se-14 arylsulfonyl, which may be substituted, Heterocyclic-sulfonyl, which may be substituted," Sz-7 cycloalkylsulfinyl, which may be substituted, ”optionally substituted Se-14, arylsulfinyl, optionally substituted heterocyclic-sulfinyl, substituted carbamoyl group, optionally substituted amino group, "Mono- or sN-S2-7 cycloalkylamino group, which may be substituted, mono- or di-C6-arylamino group, which may be substituted," mono- or di-C7-1-6 aralkylamino, group, which may be substituted , "Substituted Heterocyclic Amino Group," Substituted Se-14 Aryl Carbonylamino Group, "Substituted Sz-7 Cycloalkyl Carbonylamino Group, Substituted Heterocyclic Carbonylamino Group," "Sz-7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic-oxycarbonylamino group, which may be substituted, carbamoylamino group, which may be substituted, alkylsulfonylamino group, which may be substituted," Sz-7 cycloalkylo-sulfonyla may be substituted, a heterocyclic sulfonylamino group, which may be substituted, and a "Sb-14 arylsulfonylamino group, which may be substituted,

54504 Β1 and their substituents may be selected from the above-mentioned Substituent Group B and the following Substituent Group B ', the number of substituents ranging from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents:

[Substituent group B '] (a) C 1-10 alkyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C 1-10 alkylamino, mono- or di -Ce-arylamino, mono- or di-C2-ya aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7 -16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C1-6 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-06-14 arylcarbamoyl;

(b) C2-6 alkenyl, 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-aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkyl-carbonyl, C3-7 cycloalkyl-carbonyl, C1-8 aryl-carbonyl, C7-16 aralkyl-carbonyl, C1 -10 alkoxycarbonyl, Sb-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, S1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-arylcarbamoyl; and (c) C2-6 alkynyl, which may be substituted by one or more substituents selected from halogen atoms, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-arylamino , mono- or di-C2-is aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkylcarbonyl , C1-10 alkoxycarbonyl, C1-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfinyl, C1-10 alkylsulfinyl, We are an alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C8-arylcarbamoyl group; or its salt,

In 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 dependence or attention deficit / hyperactivity disorder.

54504 Β1 [45] Compound of formula (Ιο):

<img file="RS54504B1_D0004.tif" />

where

R¹ represents a substituent,

R² represents a substituent,

R³ represents a hydrogen atom, or a substituent,

Ring A represents an aromatic ring, which may be substituted, and

Ring B represents a 5-membered heteroaromatic ring, which may be substituted, wherein the substituent for R¹, R² or R³, chooses from substituents of an aromatic ring which may be substituted for Ring A, or substituents of a 5-membered heteroaromatic ring which may be substituted for Ring B, from the Group of Substituents A;

[Substituent group A] (1) a halogen atom;

(2) some nitro group;

(3) some cyano group;

(4) a carboxy group, which can be esterified;

(5) a C1-10 alkyl group, 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 C 3-7 cycloalkyl group, which may be substituted;

54504 Β1 (9) an Sb-a aryl group, which may be substituted;

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

(11) a C 1-4 aryl-C 2-6 alkenyl group which may be substituted;

(12) a heterocyclic group, which may be substituted;

(13) a hydroxy group;

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

(15) a C 3-7 cycloalkoxy group, which may be substituted;

(16) a C 1-6 aryloxy group, which may be substituted;

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

(18) a C1-10 alkyl-carbonyloxy group, which may be substituted;

(19) a C 1-6 alkoxy-carbonyloxy group, which may be substituted;

(20) a mono-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(21) a di-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(22) a ce-14 aryl-carbonyloxy group which may be substituted;

(23) a mono- or di-Ce-14 aryl-carbamoyloxy group, which may be substituted;

(24) a heterocyclic-oxy ​​group, which may be substituted;

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

(26) some mercapto group;

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

(28) a C 3-7 cycloalkylsulfanyl group, which may be substituted;

(29) baking a Ce-14 arylsulfanyl group, which may be substituted;

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

(31) a heterocyclic-sulfanyl group, which may be substituted;

(32) a formyl group;

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

(34) a C 3-7 cycloalkylcarbonyl group, which may be substituted;

(35) a C 1-4 arylcarbonyl group which may be substituted;

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

(37) a heterocyclic-carbonyl group, which may be substituted;

(38) a C 1-4 alkylsulfonyl group which may be substituted;

(39) a C 3-7 cycloalkylsulfonyl group, which may be substituted;

(40) a C1-4 alkylsulfonyl group, which may be substituted;

(41) a heterocyclic-sulfonyl group, which may be substituted;

54504 Β1 (42) is a C1-10 alkylsulfinyl group which may be substituted;

(43) a C 3-7 cycloalkylsulfinyl group, which may be substituted;

(44) a C 1-6 alkylsulfinyl group, which may be substituted;

(45) a heterocyclic-sulfinyl group, which may be substituted;

(46) a sulfo group;

(47) a sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) a thiocarbamoyl group;

(51) a carbamoyl group, which may be substituted;

(52) an amino, mono- or di-C1-10 alkylamino group, which may be substituted, a mono- or sN-S2-7 cycloalkylamino group, which may be a substituted mono- or di-C6-arylamino group, which may be a substituted, mono- or di-C 1-6 aralkylamino group, which may be substituted, a heterocyclic amino group, which may be substituted, a C 1-14 aryl-carbonylamino group, which may be substituted, formylamino,

C1-10 alkyl-carbonylamino group, which may be substituted, Sz-7 cycloalkyl-carbonylamino group, which may be substituted, heterocyclic-carbonylamino group, which may be substituted, Sz-7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic -oxycarbonylamino group, which may be substituted, carbamoylamino group, which may be substituted,

A C1-10 alkylsulfonylamino group, which may be substituted,

A C3-7 substituted cycloalkylsulfonylamino group, a substituted heterocyclic sulfonylamino group, a substituted C1-14 arylsulfonylamino group, and between the above-mentioned Substituent Group A, a C1-10 alkoxycarbonyl group, which may be substituted, a "C 1-10 alkyl group, which may be substituted," a C 1-6 alkenyl group, which may be substituted, a "C 1-6 alkynyl group, which may be substituted," a C 1-10 alkoxy group, which may be substituted,

54504 Β1

A C1-10 alkylcarbonyloxy group, which may be substituted,

C1-10 alkoxy-carbonyloxy group, which may be substituted, "mono-C1-10 alkyl-carbamoyloxy group, which may be substituted," di-C1-10 alkyl-carbamoyloxy group, which may be substituted, "C1-10 alkylsulfanyl a group, which may be substituted, ”We are an alkylcarbonyl group, which may be substituted,

A C1-10 alkylsulfonyl group, which may be substituted, a "C1-10 alkylsulfinyl group, which may be substituted," a C1-10 alkylcarbamoyl group, which may be substituted, a "mono- or di-C1-10 alkylamino group, which may be substituted, a "C 1-10 alkyl-carbonylamino group, which may be substituted," a topo- (C 1-10 alkyl-carbonyl) -amino group, which may be substituted, a "C 1-10 alkoxy-carbonylamino group, which may be substituted, and

C1-10 alkylsulfonylamino groups, which may be substituted, their substituents may be selected from the following Group of substituents B, and the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3, [Group of substituents B] (a ) a halogen atom;

(b) baking hydroxy group;

(c) a nitro group;

(d) a cyano group;

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

(f) a C 1-6 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 having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted;

(i) an amino group, which may be substituted;

(j) C3-7 cycloalkyl;

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

(l) some formyl;

54504 Β1 (m) some C1-10 alkylcarbonyl;

(n) a C3-7 cycloalkylcarbonyl;

(o) an Sb-14 aryl carbonyl;

(p) some C7-16 aralkylcarbonyl;

(q) a C1-10 alkoxycarbonyl;

(r) an Ce-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl;

(t) some C1-10 alkylsulfanyl;

(u) some C1-10 alkylsulfinyl;

(v) a C1-10 alkylsulfonyl;

(w) a carbamoyl group;

(x) some thiocarbamoyl;

(y) a mono- C1-10 alkylcarbamoyl;

(z) a di-C1-10 alkylcarbamoyl;

(aa) some mono- or di-C 6 aryl-carbamoyl; and (bb) a mono- or di-5- to 7-membered heterocyclic-carbamoyl having 1 to 4 heteroatoms, selected from nitrogen, sulfur and oxygen, and from the above-mentioned Substituent Group A, "Sb-14 aryloxy- carbon, which may be substituted, “C7-16 aralkyloxy-carbonyl, which may be substituted,” Sz-7 cycloalkyl - C2-6 alkynyl, which may be substituted, “Sz-7 cycloalkyl, which may be substituted,” Se- 14 aryl, which may be substituted, ”07-16 aralkyl, which may be substituted, "Se-14 aryl-C2-6 alkenyl, which may be substituted, heterocyclic group, which may be substituted," S2-7 cycloalkyloxy, which may be substituted, "Sb-1 and aryloxy, which may be substituted," 07-16 aralkyloxy, which may be substituted, "Sb- and aryl-carbonyloxy, which may be substituted," mono- or di-C1-14 aryl-carbamoyloxy, which may be substituted, heterocyclic-oxy ​​which may be substituted, aromatic heterocyclic-oxy which may be substituted,

C3-7 cycloalkylsulfanyl, which may be substituted, zz

54504 Β1

Sb-14 arylsulfanyl, which may be substituted, "C7 &lt;6 aralkylsulfanyl, which may be substituted, heterocyclic-sulfanyl, which may be substituted," Sz-7 cycloalkyl-carbonyl, which may be substituted, "Sb-14 aryl-carbonyl , which may be substituted, ”C 1 -C 16 arakyl-carbonyl, which may be substituted, heterocyclic-carbonyl, which may be substituted,” S 2-7 cycloalkylsulfonyl, which may be substituted, ”Sb-1 and arylsulfonyl, which may be substituted , ”Heterocyclic-sulfonyl, which may be substituted, "S3-7 cycloalkylsulfinyl, which may be substituted," Se-14 arylsulfinyl, which may be substituted, "heterocyclic-sulfinyl, which may be substituted," carbamoyl group, which may be substituted, "amino group, which may be substituted, a “mono- or sN-S2-7 cycloalkylamino group, which may be substituted,” a mono- or di-C6-arylamino group, which may be substituted, a “mono- or di-C7-1 aralkylamino group , which may be substituted, a substituted heterocyclic amino group, a substituted Se-14 arylcarbonylamino substituted group, a substituted C3-7 cycloalkylcarbonylamino substituted group, a substituted heterocycliccarbonylamino group, Sz- 7 cycloalkyloxy-carbonylamino group, which may be substituted, heterocyclic-oxycarbonylamino group, which may be substituted, "carbamoylamino group, which may be substituted, alkylsulfonylamino group, which may be substituted, a "Sz-7 cycloalkyl-sulfonylamino group, which may be substituted, a heterocyclic sulfonylamino group, which may be substituted, and a" Sb- and arylsulfonylamino group, which may be substituted, their substituents being selected from the group mentioned above. substituents B and the following Group of substituents B ', and the number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents:

[Substituent group B ']

54504 Β1 (a) C 1-10 alkyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C 1-10 alkylamino, mono- or di-C 6-10 arylamino, mono- or di-C2- is aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-7 10 alkoxycarbonyl, C 1-10 aryloxycarbonyl, C 7-16 aralkyloxycarbonyl, C 1-10 alkylsulfanyl, C 1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-arylcarbamoyl;

(b) C2-6 alkenyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C1-14 arylamino, mono- or di-C7-1 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C1-10 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-06-14 arylcarbamoyl; and (c) C2-6 alkynyl, which may be substituted by one or more substituents selected from halogen atoms, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-arylamino , mono- or di-C7- and aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-6 arylcarbonyl, C7-16 aralkylcarbonyl, C1 -10 alkoxycarbonyl, C5-10 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-C5-14 arylcarbamoyl groups;

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 dependence or attention deficit / hyperactivity disorder.

Advantageous effects of the present invention

The compound of the present invention has inhibitory activity against a PDE and is useful as a drug for the prevention or treatment of schizophrenia.

54504 Β1

Brief description of draft images

Figure 1. Dose-dependent graphs show an increase in cAMP (Figure 1A) and cGMP (Figure 1B) content in murine striatum, compared to comparative compound A.

Figure 2. The graphs show dose-dependent inhibition for methamphetamine (MAP) - or ΜΚ-801-induced with hyperloco-movement toward comparative compound A. Comparative compound A reduces spontaneous loco-movement (-30-0 min).

Figure 3. Graphs show recovery from ΜΚ-801-induced PPI deficits with a prepulse of 82 dB, compared to compound A.

Figure 4. The graphs show lo-801-induced hyperloco-movement inhibition in mice with the compounds.

Detailed description of the invention

The present invention will be described in detail below.

Unless otherwise specifically stated, examples of "halogens" in this application are fluorine, chlorine, bromine and iodine.

Unless otherwise specifically stated, in this application, the phrase may be halogenated or the term halogen means that one or more (e.g. 1 to 3) halogen atoms may be present as a substituent.

Unless otherwise specifically stated in this application, examples of C 1-10 alkyl (groups) are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.

Unless otherwise specifically stated, in this application, the term halogenated C1-10 alkyl (group) means C1-10 alkyl (group) which may be substituted by halogen, an example of which is trifluoromethyl.

54504 Β1

Unless otherwise specifically stated, in this application, examples of S8-e alkenyl (groups) are vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-buten-1-yl, 4- penten-1-yl and 5hexen-1-yl.

Examples of C2-6 alkynyl (groups) are ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentin-1-yl and 5hexin-1-yl.

Unless otherwise specifically stated, in this application, an example of a C3-7 cycloalkyl-C2-alkynyl (group) is cyclopropylethynyl.

Unless otherwise specifically noted, in this application, examples of C3-7 cycloalkyl (groups) are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Unless otherwise specifically stated in this application, examples of "Sb-14 aryl (groups) are suphenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl and 2-anthryl.

Unless otherwise specifically stated in this application, examples of C7-16 aralkyl (groups) are benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl and 4-biphenylmethyl.

Unless otherwise specifically stated, in this application, an example of Sb-14 aryl-C2-6 alkenyl (groups) is styryl.

Unless otherwise specifically stated in this application, a heterocyclic group (and a heterocyclic moiety in a substituent) is a non-aromatic heterocyclic group, or a peca heteroaryl group (i.e., an aromatic heterocyclic group), and examples thereof are 3- to A 14-membered heterocyclic group, having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. This heterocyclic group may be monocyclic, bicyclic or tricyclic.

Examples of a "3- to 14-membered heterocyclic group are a 3- to 14-membered aromatic heterocyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl) , 3-pyrrolyl), furyl (e.g. 2furyl, 3-furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4

54504 Β1 pyrazolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (ex. 2-oxazolyl, 4-oxazolyl, 4- , isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg 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 (eg 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, indolyl, isoindolyl . 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (e.g. 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6 -indolyl, 7-indolyl), benzo [b] furanyl (eg 2-benzo [b] furanyl, 3-benzo [b] furanyl, 4 benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [ b] furanyl, 7-benzo (b-furanyl), benzo [c] furanyl (ex. 1-benzo [c] furanyl, 4-benzo [c] furanyl, 5-benzo [c] furanyl), benzo [b] thienyl ( e.g. 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzo [c] thienyl (e.g. 1-benzo [c] thienyl, 4benzo [c] thienyl, 5-benzo [c] thienyl), indazolyl (e.g. 1-indazolyl, 2-indazolyl, 3-indazolyl, 4indazolyl, 5- indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (e.g. 1-benzimidazolyl, 2benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), 1,2-benzoisoxazolyl (e.g. 1,2-benzisoxazol-3-yl, 1,2-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-benzoisothiazolyl (e.g. 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-2- benzisothiazole

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), cinnolinyl (e.g. 3-cinolinyl, 4-cinolinyl, 5-cinolinyl, 6-cinolinyl, 7-cinolinyl, 8-cinolinyl), phthalazinyl (e.g. 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-phthayazinyl), quinazolinyl (e.g. 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl-quinolinyl), quinolinyl) 3-quinoxalinyl, 5-quinoxalinyl,

6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl), pyrazolo [1,5-a] pyridyl (eg pyrazolo [1,51] pyridin-2-yl, pyrazolo [1,5-a] pyridin-3-yl) , pyrazolo [1,5-a] pyridin-4-yl, pyrazolo [1,5-a] pyridin5-yl, pyrazolo [1,5-a] pyridin-6-yl, pyrazolo [1,5-a] pyridin-7 -yl), imidazo [1,2-a] pyridyl (prg. 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 having

54504 Β1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as tetrahydrofuryl, oxazolidinyl, imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl], 4imidazolinyl), aziridinyl (e.g. 1-aziridinyl) 2-a , azetidinyl (e.g. 1-azetidinyl, 2azetidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (e.g. 1piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (e.g. 1- azepanyl, 2-azepanyl, 3azepanyl, 4-azepanyl), azocanyl (prg. 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), diazocanil (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 dihydroquinolyl.

Unless otherwise specifically stated, in this application, examples of “5- to 10-membered heterocyclic groups are those having 5- to 10-membered among the above-mentioned 3 to 14-membered heterocyclic groups.

Unless otherwise specifically stated in this application, examples of an "aromatic heterocyclic group (and an aromatic heterocyclic moiety in a substituent) are" a 3- to 14-membered aromatic heterocyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as the heterocyclic groups mentioned above.

Unless otherwise specifically stated in this application, examples of a "non-aromatic heterocyclic group (and an aromatic heterocyclic moiety in a substituent) are a" saturated or unsaturated 3- to 14-membered non-aromatic heterocyclic group having 1 to 5 heteroatoms which are selected from nitrogen, sulfur and oxygen, such as the heterocyclic groups mentioned above.

Unless otherwise specifically stated in this application, examples of a “saturated heterocyclic group (and a saturated heterocyclic moiety in a substituent) are those that are saturated among said non-aromatic heterocyclic groups. Their specific examples are tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl and piperazinyl groups.

54504 Β1

Unless otherwise specifically stated in this application, examples of "5- to 6-membered saturated heterocyclic groups (and a saturated heterocyclic moiety in a substituent) are those having 5- to 6-membered among said saturated heterocyclic groups.

Unless otherwise specifically noted, in this application, examples of C 1-10 alkoxy (groups) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

Unless otherwise specifically stated, in this application, examples of “C3-7 cycloalkyloxy (groups) are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

Unless otherwise specifically indicated, in this application, examples of "Sb-14 aryloxy (groups) are phenyloxy, 1-naphthyloxy and 2-naphthyloxy.

Unless otherwise specifically stated, in this application, examples of C7-16 aralkyloxy (groups) are benzyloxy and phenethyloxy.

Unless otherwise specifically emphasized, in this application, examples of C1-10 alkylcarbonyloxy (groups) are acetoxy and propionyloxy.

Unless otherwise specifically stated, in this application, examples of C1-10 alkoxycarbonyloxy (groups) are methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy and butoxycarbonyloxy.

Unless otherwise specifically stated, in this application, examples of mono-C1-10 alkylcarbamoyloxy (groups) are methylcarbamoyloxy and ethylcarbamoyloxy.

Unless otherwise specifically stated, in this application, examples of "di-C1-10 alkylcarbamoyloxy" groups) are dimethylcarbamoyloxy and diethylcarbamoyloxy.

Unless otherwise specifically stated, in this application, examples of C1-4 arylcarbonyloxy (groups) are benzoyloxy and naphthylcarbonyloxy.

54504 Β1

Unless otherwise specifically stated, in this application, examples of mono- or di-Ce-aryl-carbamoyloxy (groups) are phenylcarbamoyloxy and naphthylcarbamoyloxy.

Unless otherwise specifically stated in this application, examples of a heterocyclic residue of a "heterocyclic-oxy" group are similar to those mentioned for a heterocyclic group. Specifically, examples of "heterocyclic-oxy" groups are 5- to 14-membered heterocyclic-oxy ​​(group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

Unless otherwise specifically stated in this application, examples of an aromatic heterocyclic moiety of a "heterocyclic-oxy" group are similar to "aromatic heterocyclic group" as examples of said heterocyclic group. Specifically, examples of “aromatic heterocyclic-oxy ​​(groups) are 3- to 14-membered aromatic heterocyclic-oxy ​​(groups) having 1 to 5 heteroatoms, selected from nitrogen, sulfur and oxygen.

Unless otherwise specifically stated, in this application, examples of C1-10 alkylsulfonyloxy (groups) are methylsulfonyloxy and ethylsulfonyloxy.

Unless otherwise specifically stated, in this application, examples of halogen C1-10 alkylsulfonyloxy (groups) are halogeno methylsulfonyloxy and halogeno ethylsulfonyloxy.

Unless otherwise specifically stated, in this application, examples of C 1-4 alkylsulfanyl (groups) are methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, secbutylsulfanyl and tert-butylsulfanyl.

Unless otherwise specifically stated, in this application, examples of “C3-7 cycloalkylsulfanyl (groups) are cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl and cyclohexylsulfanyl.

Unless otherwise specifically stated, in this application, examples of C 1-6 arylsulfanyl (groups) are phenylsulfanyl, 1-naphthylsulfanyl and 2-naphthylsulfanyl.

54504 Β1

Unless otherwise specifically stated, in this application, examples of C 2-6 aralkylsulfanyl (groups) are benzylsufanyl and phenethylsulfanyl.

Unless otherwise specifically stated in this application, examples of the heterocyclic radical "heterocyclic-sulfanyl (group) are similar to those mentioned for the heterocyclic group. Specifically, examples of “heterocyclic sulfanyl (groups) are a 5- to 14-membered heterocyclic-sulfanyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

Unless otherwise specifically stated, in this application, examples of C1-10 alkylcarbonyl (groups) are acetyl, propionyl and pivaloyl.

Unless otherwise specifically stated, in this application, examples of C3-10 cycloalkylcarbonyl (groups) are cyclopropylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl groups.

Unless otherwise specifically stated, in this application, examples of C5-aryl-carbonyl (groups) are benzoyl, 1-naphthoyl and 2-naphthoyl.

Unless otherwise specifically stated in this application, examples of “C7-16 aralkylcarbonyl (groups) are phenylacetyl and 3-phenypropionyl.

Unless otherwise specifically stated in this application, examples of the heterocyclic radical "heterocyclic-carbonyl" (dgire) are similar to those mentioned for the heterocyclic group. Specifically, their examples are a 3- to 14-membered heterocycliccarbonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. Further, their specific examples are picolinoyl, nicotinoyl, isonicotinoyl, 2tenoyl, 3-tenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, aziridin-1ylcarbonyl, aziridin-2-ylcarbonyl, azetine azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, azepan-1-ylcarbonyl, azepan-2-yl , azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl, azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-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

54504 Β1 diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl, 1,5-diazocan-1-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl and 1,5-diazocan-3-ylcarbonyl.

Unless otherwise specifically stated, in this application, examples of carboxy (groups) that can be esterified are carboxy, alkoxy-carbonyl, which can be substituted, C6-aryloxy-carbonyl, which can be substituted, C7-16 aralkyloxycarbonyl, which may be substituted, silyloxy-carbonyl, which may be substituted (e.g. TMS-O-CO-, TES-O-CO-, TBS-O-CO-, TIPS-O-CO-, TBDPS-O-CO-)

Unless otherwise specifically stated in this application, examples of C 1-10 alkoxycarbonyl (flues) are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

Unless otherwise specifically stated, in this application, examples of "Se- and aryloxycarbonyl (groups) are phenoxycarbonyl.

Unless otherwise specifically stated, in this application, examples of C 1 -C 6 aralkylcarbonyl (groups) are benzyloxycarbonyl and phenethyloxycarbonyl.

Unless otherwise specifically stated, in this application, examples of “C 1-10 alkylsulfonyl (groups) are methylsulfonyl and ethylsulfonyl.

Unless otherwise specifically stated, in this application, examples of “C3-7 cycloalkylsulfonyl (groups) are cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentysulfonyl and cyclohexylsulfonyl.

Unless otherwise specifically stated, in this application, examples of Se- and arylsulfonyl (groups) are phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl,

Unless otherwise specifically stated in this application, examples of the heterocyclic radical "heterocyclic-sulfonyl" group are similar to those for said heterocyclic group. Specifically, examples of a "heterocyclic sulfonyl" group are a 5- to 14-membered heterocyclic-sulfonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

54504 Β1

Unless otherwise specifically stated in this application, examples of a saturated heterocyclic moiety of a saturated heterocyclic-sulfonyl (group) are similar to those mentioned for a heterocyclic group. Specifically, examples of "heterocyclic-sulfonyl" groups are a 5- to 14-membered heterocyclic-sulfonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

Unless otherwise specifically stated, in this application, examples of C 1-4 alkylsulfinyl (groups) are methylsulfinyl and ethylsulfinyl.

Unless otherwise specifically stated, in this application, examples of “C3-7 cycloalkylsulfinyl (groups) are cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsufinyl and cyclohexylsulfinyl.

Unless otherwise specifically stated, in this application, examples of Ce-14 arylsulfinyl (groups) are phenylsulfinyl, 1-naphthylsulfinyl and 2-naphthylsulfinyl.

Unless otherwise specifically stated, in this application, examples of the heterocyclic heterocyclic-sulfinyl (group) moiety are similar to those mentioned for the heterocyclic group. Specifically, examples of "heterocyclic sulfinyl" groups are a 5- to 14-membered heterocyclic-sulfinyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

Unless otherwise specifically stated in this application, examples of "C1-10 alkyl-carbamoyl (groups) are methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl.

Unless otherwise specifically stated, in this application, examples of "mono- or di-C1-10 alkylamino (groups) are methylamino, ethylamino, propylamino, dimethylamino and diethylamino.

Unless otherwise specifically stated, in this application, examples of “C 1-10 alkylcarbonylamino (groups) are acetylamino, propionylamino and pivaloylamino.

Unless otherwise specifically stated in this application, examples of a heterocyclic residue of a “heterocyclic-amino (group) are similar to said heterocyclic group. An example of a "heterocyclic-amino (group) is 2-r1pR] katJpo.

54504 Β1

Unless otherwise specifically stated in this application, examples of "heterocycliccarbonyl" heterocyclic-carbonylamino (groups) are those similar to said heterocyclic-carbonyl. Examples of "heterocyclic-carbonylamino (groups) are pyridylcarbonylamino.

Unless otherwise specifically stated in this application, examples of a "heterocyclic (group) in" heterocyclic-oxycarbonylamino (group) are similar to those mentioned for a heterocyclic group. Examples of "heterocyclic oxycarbonylamino (groups) are 2-pyridyloxycarbonylamino.

Unless otherwise specifically stated in this application, the examples of a “heterocyclic (group) in a heterocyclic-sulfonylamino (group) are similar to those mentioned for a heterocyclic group. An example of a "heterocyclic-sulfonylamino (group) is 2-pyridylsulfonylamino.

Unless otherwise specifically stated in this application, “C1-10 alkoxycarbonylamino (group) represents methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino and butoxycarbonylamino.

Unless otherwise specifically stated, in this application, examples of C1-10 alkylsulfonylamino (groups) are methylsulfonylamino and ethylsulfonylamino.

Unless otherwise specifically stated in this application, examples of “mono- or sN-S2-7 cycloalkylamino (groups) are cyclopropylamino, cyclopentylamino and cyclohexylamino.

Unless otherwise specifically stated, in this application, examples of “C3-7 cycloalkylcarbonylamino (groups) are cyclopropylcarbonylamino, cyclopentylcarbonylamino and cyclohexylcarbonylamino.

Unless otherwise specifically stated, in this application, examples of C3-7 cycloalkyloxycarbonylamino (groups) are cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino and cyclohexyloxycarbonylamino.

54504 Β1

Unless otherwise specifically stated, in this application, examples of “Sz-7 cycloalkylsulfonylamino (groups) are cyclopropylsulfonylamino, cyclopentylsulfonylamino and cyclohexylsulfonylamino.

Unless otherwise specifically stated, in this application, examples of mono- or di-Ce in arylamino (groups) are phenylamino and diphenylamino.

Unless otherwise specifically stated, in this application, an example of a “mono- or di-C 2 -E aralkylamino (group) is benzylamino.

Unless otherwise specifically stated, in this application, examples of Sb-14 arylcarbonylamino (groups) are benzoylamino and naphthoylamino.

Unless otherwise specifically stated in this application, examples of Se-m arylsulfonylamino (groups) are phenylsulfonylamino, 2-naphthylsulfonylamino and 1-naphthylsulfonylamino.

Symbols in the above - mentioned formulas (Formula (l₀) and Formula (I)) will be explained below.

In the above formula, R¹ represents a substituent selected from the group of substituents A described below.

[Substituent group A] (1) a halogen atom;

(2) some nitro group;

(3) some cyano group;

(4) a carboxy group, which can be esterified;

(5) a C 1-10 alkyl group, which may be substituted;

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

(7) a C2-6 alkynyl group, which may be substituted, e.g., a C3-7 cycloalkyl - C2-6 alkynyl group, which may be substituted;

(8) a C 3-7 cycloalkyl group, which may be substituted;

54504 Β1 (9) a C1-6 aryl group, which may be substituted;

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

(11) a C 1-6 aryl-C 2-6 alkenyl group, which may be substituted;

(12) a heterocyclic group, which may be substituted;

(13) a hydroxy group;

(14) a C 1-4 alkoxy group, which may be substituted;

(15) a C 3-7 cycloalkoxy group, which may be substituted;

(16) a C 1-6 aryloxy group, which may be substituted;

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

(18) a C1-10 alkyl-carbonyloxy group, which may be substituted;

(19) a C1-10 alkoxy-carbonyloxy group, which may be substituted;

(20) a mono-C1-10 alkylcarbamoyloxy group, which may be substituted;

(21) a di-C 1-10 alkyl-carbamoyloxy group, which may be substituted;

(22) a Ce-14 aryl-carbonyloxy group, which may be substituted;

(23) a mono- or di-Ce-14 aryl-carbamoyloxy group, which may be substituted;

(24) an optionally substituted heterocyclic-oxy ​​group (e.g., an optionally substituted aromatic heterocyclic-oxy ​​group) (25) an optionally substituted C1-10 alkylsulfonyloxy (group) ”(eg halogen C1-10 alkylsulfonyloxy (group which may be substituted);

(26) some mercapto group;

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

(28) a baking O3-7Cycloalkylsulfanyl group, which may be substituted;

(29) a Ce-14 arylsulfanyl group, which may be substituted;

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

(31) a heterocyclic-sulfanyl group, which may be substituted;

(32) a formyl group;

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

(34) a C 3-7 cycloalkylcarbonyl group, which may be substituted;

(35) a C 1-6 arylcarbonyl group, which may be substituted;

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

(37) a heterocyclic-carbonyl group, which may be substituted;

(38) a C 1-4 alkylsulfonyl group, which may be substituted;

(39) a C 3-7 cycloalkylsulfonyl group, which may be substituted;

54504 Β1 (40) is a C5-14 arylsulfonyl group, which may be substituted;

(41) a heterocyclic-sulfonyl group, which may be substituted;

(42) a C1-10 alkylsulfinyl group, which may be substituted;

(43) a C 3-7 cycloalkylsulfinyl group, which may be substituted;

(44) a Se-m arylsulfinyl group, which may be substituted;

(45) a bake heterocyclic-sulfinyl group, which may be substituted;

(46) a sulfo group;

(47) a sulfamoyl group;

(48) a sulfinamoyl group;

(49) a sulfenamoyl group;

(50) a thiocarbamoyl group:

(51) a carbamoyl group, which may be substituted [e.g. alkyl-carbamoyl group, which may be substituted] (52) an amino, mono- or di-C1-10 alkylamino group, which may be substituted, mono- or di-S2-? a substituted cycloalkylamino group, a substituted mono- or di-C5-arylamino substituted group, a substituted mono- or di-C2-aralkylamino group, a substituted heterocyclic amino group,

A ce-14 aryl-carbonylamino group, which may be substituted, formylamino,

A C1-10 alkyl-carbonylamino group, which may be substituted (e.g. mono- (C1-10 alkyl-carbonyl) -amino group, which may be substituted),

S2-7, which may be substituted cycloalkyl-carbonylamino, optionally substituted heterocyclic-carbonylamino,

S2-7, which may be substituted cycloalkyloxy-carbonylamino, which may be substituted, heterocyclic-oxycarbonylamino, which may be substituted, carbamoylamino, which may be substituted,

A C1-10 alkylsulfonylamino group, which may be substituted,

S2-7 substituted cycloalkyl-sulfonylamino group, optionally substituted heterocyclic sulfonylamino group, optionally substituted C1-14 arylsulfonylamino group]

Among the above-mentioned Group of Substituents A, are

54504 Β1 ”C1-6 alkoxy-carbonyl group, which may be substituted,” C1-10 alkyl group, which may be substituted, ”S2-b alkenyl group, which may be substituted,

A C2-6 alkynyl group which may be substituted, a C1-10 alkoxy group which may be substituted,

C1-10 alkyl-carbonyloxy group, which may be substituted, "C1-10 alkoxy-carbonyloxy group, which may be substituted, mono- C1-10 alkyl-carbamoyloxy group, which may be substituted, di C1-10 alkyl-carbamoyloxy group , which may be substituted, a C1-10 alkylsulfanyl group, which may be substituted,

A C1-10 alkylcarbonyl group, which may be substituted, a C1-10 alkylsulfonyl group, which may be substituted,

C1-10 alkylsulfinyl group, which may be substituted, "C1-10 alkyl-carbamoyl group, which may be substituted," mono- or di-C1-10 alkylamino group, which may be substituted, "C1-10 alkyl-carbonylamino group , which may be substituted, a mono- (C1-10 alkylcarbonyl) -amino group, which may be substituted, a C1-10 alkoxycarbonylamino group, which may be substituted, and a C1-10 alkylsulfonylamino group, which may be substituted ,, its substituents can also be selected from the following Group of substituents B. The number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3, and even more preferably 1.

[Substituent group B]

A group of substituents B consists of (a) a halogen atom;

(b) a hydroxy group;

(c) a nitro group;

(d) a cyano group;

(e) a C 1-10 aryl group which may be substituted (a C 1-10 aryl group may be substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-10 alkyl, which may be to be halogenated, mono- or di49

54504 Β1

C1-10 alkylamino, mono- or di-C5-arylamino, mono- or di-C1-6 alkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C 6-10 arylcarbonyl, C 7-16 aralkylcarbonyl, C 1-10 alkoxycarbonyl, C 6-10 aryoxycarbonyl, C 7-16 aralkyloxycarbonyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-14 arylcarbamoyl);

(f) an optionally substituted Sb-14 aryloxy group (“The C6-aryloxy group may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C1-10 alkyl which may be halogenated , monoyl di-C1-10 alkylamino, mono- or di-C1-4 arylamino, mono- or di-C7-6 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkyl -carbonyl, Sb-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C1-10 alkoxy-carbonyl, Sb-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfinyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-Ce-14 aryl -carbamoyl);

(g) a C7-16 aralkyloxy group, which may be substituted ("a C7-16 aralkyloxy group may be substituted with one or more substituents selected from halogen atoms, hydroxy, cyano, amino, C1-10 alkyl which may be substituted. halogenated, mono or di-C1-10 alkylamino, rriono- or di-C6-arylamino, mono- or di-C2-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl,

C3-7 cycloalkylcarbonyl, C1-6 arylcarbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C1-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfinyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C10 alkylcarbamoyl and mono- or di-C1-4 aryl-carbamoyl); (h) a mono- or di-5- to 10-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (eg. furyl, pyridyl, thienyl, pyrrolidino, 1-piperidinyl, 4piperidyl, piperazinyl, 1-morpholinyl, 4-thiomorpholinyl, azepan-1-yl, azocan-1-yl, azonan-1-yl, 3,4-dihydroisoquinoline-2- il), which may be substituted by a “mono or di5- to 10-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen may be substituted by one or more substituents selected from halogen, hydroxy , cyano, amino, halogenated C1-10 alkyl, mono- or di-C1-10 alkylamino, mono- or di-C1-4 arylamino, mono- or di- C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3 -7 cycloalkylcarbonyl, C5-14 arylcarbonyl, C7-16

54504 Β1 aralkylcarbonyl, C1-10 alkoxycarbonyl, C1-10 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10-allyl and a mono- or di-C6-arylcarbamoyl group);

(i) an amino group, which may be substituted [prg. amino group, which may be substituted with one or two substituents selected from the group consisting of C1-10 alkyl, C2-6 alkenyl, Sb-14 aryl, C7-16 aralkyl, heterocyclic group and heterocyclic-alkyl group (C1-10 alkyl, C2-6 alkenyl, C1-6 aryl, C7-16 aralkyl, heterocyclic group and heterocyclic alkyl group may be substituted by halogen atom, hydroxy, cyano, amino, C1-10 alkyl which can be halogenated (but not alkyl and alkenyl substituents), mono- or di-C1-10 alkylamino, mono- or di-C1-14 arylamino, mono- or di- C7-16 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-10 aryl -carbonyl, C7-16 aralkylcarbonyl, C1-10 alkoxycarbonyl, C3-7 cycloalkyloxycarbonyl, C1-6 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C3-7 cycloalkylsulfanyl, C1-10 alkylsulfin , C3-7 cycloalkylsulfinyl, C1-10 alkylsulfonyl, C3-7 cycloalkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl, mono- or di-C 1-4 aryl-carbamoyl group). Heterocyclic and heterocyclic in heterocyclic-alkyl are the same as in the above-mentioned heterocyclic group];

(j) C 1-7 cycloalkyl;

(k) an optionally substituted C 1-10 alkoxy ("C 1-10 alkoxy may be substituted with one or more substituents selected from halogen, hydroxy, amino, mono- or di-C 1-10 alkylamino, mono - or di-C6-arylamino, C3-7 cycloalkyl, S1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkylcarbonyl, C1 -10 alkoxycarbonyl, Sb-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-arylcarbamoyl);

(l) some formyl;

(m) some C1-10 alkylcarbonyl (e.g. acetyl);

(n) a C3-7 cycloalkylcarbonyl;

(o) an Sb-14 aryl carbonyl;

(p) some C7-16 aralkylcarbonyl;

(q) some C 1-4 alkoxycarbonyl;

54504 Β1 (g) some Sb-14 aryloxycarbonyl;

(s) a C7-16 aralkyloxycarbonyl;

(t) some C1-10 alkylsulfanyl;

(u) some C1-10 alkylsulfinyl;

(v) a C1-10 alkylsulfonyl;

(w) a carbamoyl group;

(x) some thiocarbamoyl;

(y) some mono-C1-10 alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl);

(z) a di-C1-10 alkylcarbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl);

(aa) mono- or di-C 6 -amyl aryl-carbamoyl (e.g. phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl); and (bb) a mono- or di-5- to 7-membered heterocyclic-carbamoyl having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (e.g. 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2- thienylcarbamoyl, 3-thienylcarbamoyl).

Among those mentioned above in the Group of Substituents A, there are also "Se-14 aryloxy-carbonyl, which may be substituted," S7-1b aralkyloxy-carbonyl, which may be substituted, "S2-7 cycloalkyl-C2-6 alkynyl, which may be substituted, "C3-7 cycloalkyl, which may be substituted,

Sb-14 aryl, which may be substituted, "Ο? -16 aralkyl, which may be substituted," Sb-14 aryl-C2-6 alkenyl, which may be substituted, heterocyclic group, which may be substituted "," Sz- 7 cycloalkyloxy, which may be substituted, "Sb-14 aryloxy, which may be substituted," 07-16 aralkyloxy, which may be substituted,

Sb-14 aryl-substituted aryl-carbonyloxy, "mono- or di-C6-aryl-substituted aryl-carbamoyloxy," substituted heterocyclic-oxy, optionally substituted aromatic heterocyclic-oxy ​​"," S2-7 cycloalkylsulfanyl, which may be substituted,

54504 Β1 ”Sb-i arylsulfanyl, which may be substituted,

C7-16 aralkylsulfanyl, which may be substituted, "heterocyclic-sulfanyl, which may be substituted," Sz-7 cycloalkyl-carbonyl, which may be substituted, "C1-14 aryl-carbonyl, which may be substituted," 07-16 aralkyl-substituted aralkyl-carbonyl, optionally substituted heterocyclic-carbonyl, "Sz-7 cycloalkylsulfonyl, which may be substituted," C1-4 alkylsulfonyl, which may be substituted, heterocyclic-sulfonyl, which may be substituted, C3-7 cycloalkylsulfinyl, which may be substituted, "Se-14 arylsulfinyl, which may be substituted, heterocyclic-sulfinyl, which may be substituted, carbamoyl group, which may be substituted, amino group, which may be substituted," mono- or a sN-Sz-7 cycloalkylamino group, which may be substituted, a “mono- or di-C6-arylamino group, which may be substituted,” a mono- or di-C7-w aralkylamino group, which may be substituted, a heterocyclic amino group ,, which may be substituted, a "C8-14 aryl-carbonylamino group, which may be substituted," a Sz-7 cycloalkyl-carbonylamino group, which may be substituted, a "heterocyclic-carbonylamino group, which may be substituted," a C3-7 cycloalkyloxy- a substituted carbonylamino group, an optionally substituted heterocyclic-oxycarbonylamino group, an optionally substituted carbamoylamino group, an optionally substituted alkylsulfonylamino group,

A C3-7 cycloalkylsulfonylamino group, which may be substituted, a heterocyclic sulfonylamino group, which may be substituted, and a Sb-14 arylsulfonylamino group, which may be substituted, its substituents being selected from substituents of the aforementioned Substituent Group B and the following Substituent groups B '. The number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents and even more preferably 1 substituent.

54504 Β1 [Substituent group B ']

The group of substituents B 'consists of (a) C1-10 alkyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C 1-10 alkylamino, mono- or di-C 1 -C 6 arylamino, mono- or di-C7-6 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkyl- carbonyl, C1-10 alkoxycarbonyl, Sb-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C1-10 alkylcarbamoyl and mono- or di-C6-arylcarbamoyl;

(b) C2-6 alkenyl, which may be substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C1-10 alkylamino, mono- or di-C6-arylamino , mono- or di-C7-aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C1-6 arylcarbonyl, C7-16 aralkylcarbonyl , C1-10 alkoxycarbonyl, C1-14 aryloxycarbonyl, C7-16 aralkyloxycarbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1-10 alkylcarbamoyl and mono- or di-C 1-4 arylcarbamoyl; and (c) C 2-6 alkynyl, which may be substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, mono- or di-C 1-10 alkylamino, mono- or di-C 1 -C 1 atoms. in arylamino, mono- or di-C7-1 aralkylamino, C3-7 cycloalkyl, C1-10 alkoxy, formyl, C1-10 alkylcarbonyl, C3-7 cycloalkylcarbonyl, Sb-14 arylcarbonyl, C7-16 aralkyl -carbonyl, C1-10 alkoxy-carbonyl, C1-10 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, C1-10 alkylsulfanyl, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C10 alkylcarbamoyl and mono- or di-C1-14 arylcarbamoyl groups.

Among them, it is preferred that R¹ represents a C1-10 alkyl group, which may be substituted, a C3-7 cycloalkyl group, which may be substituted, a C1-14 aryl group, which may be substituted, a non-aromatic heterocyclic group, which may be substituted, or a heterocyclic group, which may be substituted.

54504 Β1

Among these, it is specifically preferred that R¹ represents, for example, a phenyl group, which may be substituted by 1 to 5 substituents selected from halogen atoms, 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 more preferably a phenyl group, which may be substituted with 1 to 5 halogen atoms.

In another aspect of the present invention, special R¹ is, for example, a 5- or 6-membered aromatic group (preferably a phenyl group, a pyridyl group), which may be substituted by one or more substituents selected from:

a halogen atom (preferably a chlorine atom, a fluorine atom), a cyano group, a hydroxy group, a C 1-10 alkyl group (preferably a methyl group, an isobutyl group), which may be substituted, a C 1-10 alkoxy group (preferably methoxy group), which may be substituted, a C1-10 alkylsulfanyl group, 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, are preferred.

The number of substituents ranges from 1 to the maximum number that can be substituted, more preferably from 1 to 3 substituents, and even more preferably 1 substituent.

They are particularly preferred as R¹, for example, se-m aryl, which may be substituted, and heteroaryl, which may be substituted.

Preferred R¹ is, for example, a phenyl group, which is substituted with 1 or more (preferably, 1 to 5) substituents selected from (a) a C 1-10 alkyl group (e.g. isopropyl, isobutyl), and

54504 Β1 (b) halogen atoms (eg chlorine, fluorine), C1-10 alkyl groups (eg methyl), C1-10 alkoxy groups (eg methoxy) ·

In the above-mentioned formula R² represents a substituent selected from the above-mentioned Group of Substituents A.

Among them, the preferred R², for example, is a halogen atom, a hydroxy group, a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted, more preferably a C1-10 alkoxy group, which may be substituted with one or more substituents selected from a halogen atom, a C1-10 alkoxy group and a C3-7 cycloalkyl group, and more preferably a C1-10 alkoxy group.

In another aspect of the present invention, in particular R², for example represents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxy group, (iv) a C 1-10 alkyl group, which may be substituted by one or more substituents selected from a halogen atom , hydroxy groups, amino groups and C1-10 alkoxy groups, (v) an amino group, which may be mono- or di-substituted with a C1-10 alkyl group, or (vi) a C1-10 alkoxy group, which may be substituted with one or more substituents selected from the cyano group, amino groups, C1-10 alkoxy groups, hydroxy groups, halogen atoms, and preferably a C3-7 cycloalkyl group, and, for example, (i) a hydrogen atom, (ii) a hydroxy group, (iii) a C1-10 alkyl group. a group (e.g. methyl), or (iv) a C1-10 alkoxy group (eg methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, difluoromethoxy), which may be substituted with one or more substituents selected from halogen atoms, and C3 A -7 cycloalkyl group is more preferred.

54504 Β1

In the above formula, R³ represents a hydrogen atom or a substituent selected from the above-mentioned Group of Substituents A.

Among them, the desirable R³ is, for example, a halogen atom, a hydroxy group, a C1-10 alkyl group which may be substituted, or a C1-10 alkoxy group which may be substituted.

Specifically, among them the preferred R³ is, for example, a hydrogen atom, or a C1-10 alkoxy group, which may be substituted, more preferably a hydrogen atom, or a C1-10 alkoxy group, and more preferably a hydrogen atom.

In another aspect of the present invention, as R³, particularly preferred are, for example, (i) a hydrogen atom, (ii) a halogen atom, (iii) a C 1-10 alkyl group, which may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, an amino group and C1-10 alkoxy groups, (iv) an amino group, which may be mono- or di-substituted with a C1-10 alkyl group, or (vi) a C1-10 alkoxy group, which is preferred and more preferred is, for example, a hydrogen atom and a C1-10 alkyl group (e.g. methyl).

In the above-mentioned formula, Ring A represents an aromatic ring, which may be substituted,

This "aromatic ring" in the substituted aromatic ring is preferably a 5 to 16 membered aromatic ring, more preferably a 5 to 6 membered aromatic ring, and more preferably a 6-membered aromatic ring.

This "substituted aromatic ring" in the substituted aromatic ring represented in Ring A, for example, comprises: (i) an aromatic cyclic ring

54504 Β1 a hydrocarbon, (ii) an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

Said (i) aromatic cyclic hydrocarbons include, for example, Cs-14 aromatic cyclic hydrocarbons, such as benzene, naphthalene, anthracene, phenanthrene, acenaphthylene (Sb-12 aromatic cyclic hydrocarbons are preferred, and benzene is particularly preferred).

Said (ii) aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, includes, for example, 5- or 6-membered aromatic monocyclic heterocyclic rings, such as furan, thiophene, pyrrole,

1,3-oxazole, isoxazole, 1,3-thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 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 1 to 2 of said 5 to 6 membered aromatic monocyclic heterocyclic rings (preferably 1 ring) with 1 to 2 benzene rings) , or heterocyclic rings formed by condensation of 2 to * said, identical 5- to 6-membered aromatic monocyclic heterocyclic rings or different heterocyclic rings), such as benzofuran, isobenzofuran, benzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, carinyl, purtharidine, phthalase, phthalazine , β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatine, 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 [1,2-a] pyrimidine, 1,2,4-triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-b] pyridazine).

When, (ii) an aromatic heterocyclic ring, having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, contains nitrogen, such aromatic heterocyclic ring may form an N-oxide.

Among these, benzene, pyridine, pyridazine, pyrimidine, pyrazine, pyridine N-oxide are preferred,

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

54504 Β1 tetrazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, isothiazole, 1,3-oxazole, 1,3thiazole, 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, 1Himidazopyridine, 1H-imidazopyrazine, triazine, isoquinoline, benzothiadiazole, benzisoxazole, benzisothiazole, indazole, purine, isoquinoline, phthalazine, naphthyridine, cinnoline, pteridine or the like, and benzene or pyridine, for example, is particularly preferred, and benzene is most preferred.

Substituents of an "aromatic ring" which may be substituted, such as that set forth in Ring A, for example, include substituents selected from those in the aforementioned Substituent Group A.

Particularly preferred examples of substituents of an "aromatic ring" which may be substituted are (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 up to 3 nitrogen atoms as heteroatoms, which may be substituted, (5) a C1-10 alkylsulfonyl group, which may be substituted, (6) ) a S2-7 cycloalkyl group, which may be substituted, (7) a cyano group, (8) a carbamoyl group which may be substituted, (9) a C 5 substituent alkylsulfonyloxy group, (10) a C 3-7 cycloalkyl-C 1-6 alkynyl group. a group which may be substituted, (11) a tetrahydropyranyl group which may be substituted, (12) a dihydropyranyl group which may be substituted, (13) a mono- (C1-10 alkylcarbonyl) -amino group, which it cannot be substituted, (14) an optionally substituted C 1-10 alkoxycarbonyl group, (15) an optionally substituted C 1-10 alkylsulfinyl group, (16) a substituted C 1-10 alkylsulfanyl group.

54504 Β1

It will be apparent to one of ordinary skill in the art that a "4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms in a" 4- to 6-membered heterocyclic group containing 0 or 1 substituent oxygen atom and 1 to 3 nitrogen atoms as heteroatoms are included in the "heterocyclic group" of the substituted heterocyclic group.

Preferably the number of substituents ranges from 1 to 5.

The substituents in the "optionally substituted heterocyclic group" are one or more, preferably in the range 1 to 5, more preferably in the range 1 to 3, more preferably one or two.

When the number of substituents is two or more, these substituents in Ring A may be combined to form a ring, which may be substituted. A "ring" in the ring that may be substituted includes a 5- to 6-membered heterocyclic ring containing one nitrogen atom or two oxygen atoms as hetero atoms.

This "ring" may be substituted with one or more (preferably, 1 to 5) substituents selected from Group A substituents.

In another aspect of the present invention, a preferred example of these substituents in the substituted aromatic ring represented in Ring A are a halogen atom (preferably a halogen atom), a cyano group, a hydroxy group, a C 1-10 alkyl group, which may be substituted (preferably a Smo alkyl group, which may be substituted by 1 to 3 halogen atoms [prg, trifluoromethyl group]), or a substituted Smo alkoxy group, preferably a Smo alkoxy group, which may be substituted by 1 to 3 halogen atoms [e.g. methoxy group, difluoromethoxy group]), let carbamoyl group

54504 Β1 a heterocyclic-oxy ​​group (preferably a 5- to 10-membered heterocyclic-oxy ​​group containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur [e.g. benzimidazolyloxy group]), a C1-10 alkylsulfanyl group, which may be substituted, a C1-10 alkylsulfinyl group, which may be substituted, a C1-10 alkylsulfonyl group, which may be substituted (preferably a C1-10 alkylsulfonyl group [e.g. methylsulfonyl group]), a heterocyclic-sulfonyl group (preferably a 5- to 6-membered saturated heterocyclic-sulfonyl group, containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur [e.g. morpholinylsulfonyl group]), peka an optionally substituted amino group, a C3-7 cycloalkyl group (preferably C3-7 cycloalkyl [prg. cyclohexyl]) and a saturated heterocyclic group (preferably a 5- to 6-membered saturated heterocyclic group containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur [e.g. morpholinyl group and piperidyl group]).

Preferably, Ring A, for example, represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C1-10 alkyl group, which may be substituted, ( 3) a C 1-10 alkoxy group which may be substituted, (4) a C 3-7 cycloalkyl group, (5) a halogen C 1-10 alkylsulfonyloxy group, (6) a C 3-7 cycloalkyl-C 2-6 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 may be substituted by one or more substituents selected from a halogen atom, a hydroxy group, an oxo group, a C 1-4 alkoxycarbonyl group, a C1-10 alkoxy groups which may be substituted and some C1-10 alkyl groups which may be substituted.

More preferably, Ring A, for example, represents a benzene ring, which may be substituted with 1 to 5 substituents selected from

54504 Β1 (1) a halogen atom, (2) a C 1-10 alkyl group, which may be substituted by 1 to 3 halogen atoms, (3) a C 1-10 alkoxy group, which may be substituted by 1 to 3 halogen atoms, (4 ) a S2-7 cycloalkyl group, (5) a halogen C1-10 alkylsulfonyloxy group, (6) a S2-7 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, and which may be substituted with 1 to 4 substituents selected from a halogen atom, a hydroxy group, an oxo group, a C1-10 alkoxycarbonyl group, a C1-10 alkoxy group, a halogen substituent and some A C1-10 alkyl group, which may be substituted by halogen.

It is also preferred that Ring A, for example, represents 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 A 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which may be substituted by 1 to 4 substituents selected from halogen atoms, some hydroxy groups, some oxo groups, some C1 -10 alkoxycarbonyl groups, some C1-10 alkoxy groups which may be substituted by halogen and some C1-4 alkyl groups which may be substituted by halogen.

As a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, for example, a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a pyrazolyl group, a dihydropyrazolyl group are preferred. group, let the piperides! a group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

In another aspect of the present invention, as a particular Ring A, for example, a 5- to 6-membered aromatic group is preferred, which may be substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy group,

54504 Β1

We are substituted alkyl groups, substituted C1-10 alkoxy substituted groups, carbamoyl groups, substituted C1-10 alkylsulfanyl groups, substituted C1-10 alkylsulfinyl groups, C1-10 alkylsulfonyl groups , which may be substituted, heterocyclic-sulfonyl groups, amino-substituted groups, C3-7 cycloalkyl groups and saturated heterocyclic groups, and more particularly preferably a 5- to 6-membered aromatic group (e.g. phenyl, pyridyl), which may be substituted by one or more substituents selected from (a) a halogen atom (eg chlorine, fluorine), (b) a cyano group, (c) a C 1-10 alkyl group, which may be substituted by 1 to 3 halogen atoms (e.g. methyl, trifluoromethyl), (d) a C 3-7 cycloalkyl group (e.g. methyl, trifluoromethyl), (e) a C 1-4 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 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur (eg morpholinyl, benzimidazolyl, piperidinyl), (g) a C1 -10 alkyl sulfonyl group (e.g. methylsulfonyl), (h) a 5- to 10-membered heterocyclic sulfonyl group containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur (e.g. morpholinylsulfonyl), and (i) a carbamoyl group.

In the above-mentioned formula, Ring B represents a 5-membered aromatic heterocyclic ring, which may be substituted (also referred to as a 5-membered heteroaromatic ring, which may be substituted).

Examples of the 5-membered aromatic heterocyclic ring which may be substituted, represented by Ring B, are 5-membered aromatic heterocyclic rings containing 1 to 4 hetero atoms (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). Among these, pyrazole, triazole and tetrazole are preferred, and pyrazole is most preferred.

54504 Β1

Substituents of the 5-membered aromatic heterocycle represented in Ring B, for example, include substituents selected from the above-mentioned substituents of Group A substituents.

Preferred examples of these substituents are a halogen atom, a C1-10 alkyl group, which may be substituted, and a C1-10 aryl group, which may be substituted, and more preferred examples are a halogen atom, a C1-10 alkyl group and a A C1-10 aryl group, and an even more preferred example is a C1-10 alkyl group (eg methyl).

It is also preferred that Ring B does not have such a substituent. In other words, Ring B has only substituents as shown in general formula (lo).

Preferably, Ring B is a 5-membered aromatic nitrogen-containing heterocyclic ring having 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur, which may be substituted by a C 1-10 alkyl group (e.g. methyl ) (e.g. pyrazole, triazole, tetrazole).

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

In another aspect of the present invention, it is preferred that Ring B represents a 5 membered aromatic heterocyclic ring, which contains nitrogen and has 1 to 3 nitrogen atoms (eg pyrazole, triazole, tetrazole), which may be substituted by a C 1-4 alkyl group ( methyl).

More preferably, examples of substituents, residues and rings, as described in this application, are used in combination.

54504 Β1

For example, the following compounds, i.e., compounds (10-A), (10-B), (10-C), (10-D), (10-E), (10-F) and (10-G) ) are preferred as compound (lo).

[Compound (IO-A)]

The compound (s) described above, where

R¹ represents a phenyl group, which may be substituted with 1 to 5 substituents, selected from a halogen atom, a C 1-10 alkyl group which may be substituted and a C 1-10 alkoxy group which may be substituted,

R² represents a halogen atom, a hydroxy group, a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted, R³ represents a hydrogen atom, or a C1-10 alkoxy group, which may be substituted,

Ring A represents a benzene ring, which may be substituted with 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 a 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, which may be substituted, (5) a C1-10 alkylsulfonyl group , which may be substituted, (6) an optionally substituted C 3-7 cycloalkyl group, (7) a cyano group, (8) an optionally substituted carbamoyl group, (9) an optionally substituted C 1-10 alkylsulfonyloxy group, ( 10) a C 3-7 cycloalkyl-C 2-6 alkynyl group, which may be substituted, (11) a tetrahydropyranyl group, which may be substituted, (12) a dihydropyranyl group, which may be substituted, (13) a mono- C1-10 alkylcarbonyl) -amino group, which may be substituted, (14) a substituted 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, and

54504 Β1

Ring Β represents an imidazole ring, a pyrazole ring, a triazole ring or a tetrazole ring, each of which may be substituted with 1 to 3 substituents selected from a halogen atom and a C 1-10 alkyl group, which may be substituted by halogen , and the substituent options are described above.

[Compound (I0-B)]

In the compound described above (10-A), are

Ring A represents a benzene ring, which may be substituted with 1 to 5 substituents selected from (1) a halogen atom, (2) a C 1-4 alkyl group, which may be substituted, (3) a C 1-4 alkoxy group, which may be substituted. be substituted, (4) a C2-10 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 group. heterocyclic group, containing 0 or 1 oxygen atom and up to 3 nitrogen atoms as heteroatoms, which may be substituted by one or more substituents selected from halogen atoms, a hydroxy group, an oxo group, a C 1-4 alkoxycarbonyl group, a C 1 -10 substituent alkoxy groups and some substituted C1-10 alkyl groups, and substituent options are described above [Compound (I0-C)]

In the compound described above (I0), are

R¹ represents 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 represents 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 represents a hydrogen atom, or a C1-10 alkoxy group,

54504 Β1

Ring Α represents a benzene ring which may be substituted by 1 to 5 substituents selected from (1) a halogen atom, (2) an S-mo alkyl group, which may be substituted by 1 to 3 halogen atoms, (3) peka is a alkoxy group which may be substituted by 1 to 3 halogen atoms, (4) a C3-7 cycloalkyl group, (5) a halogen C1-10 alkylsulfonyloxy group, (6) a C3-7 cycloalkyl-C2-6 alkynyl group. 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 may be substituted by 1 to 4 substituents selected from halogen atoms, a hydroxy group, an oxo group, a C1-10 alkoxycarbonyl group , some S-mo alkoxy group which may be substituted by halogen and some C 1-10 alkyl group which may be substituted by halogen,

Ring B represents a pyrazole ring, which may be further substituted with 1 to 3 substituents selected from a halogen atom and a C 1-4 alkyl group, which may be substituted by halogen.

[Compound (I0-D)]

In the compound described above (I0), are

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

R² represents a C1-10 alkoxy group,

R³ represents a hydrogen atom,

Ring A represents a benzene ring 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 an oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which may be substituted by 1 to 4 substituents selected from a halogen atom, a hydroxy group, an oxo group, a C1-10 alkoxycarbonyl group, peke a C1-6 alkoxy group which may be substituted by halogen and a C1-4 alkyl group which may be substituted by halogen,

54504 Β1

Ring Β represents a pyrazole ring.

Here, as a 4- to 6-membered heterocyclic group containing 0 ίίί 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, for example, a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a pyrazolyl group, a dihydropyrazolyl group are preferred. a group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

[Compound (I0-E)]

In the compound described above (I0), are

R¹ represents an aromatic group, which is within the scope of the definition of substituent described above for Substituent Group A, and which may be substituted,

Ring A represents an aromatic ring substituted with (a) one substituent selected from (1) an optionally substituted S 2-4 cycloalkyl group, and (2) a 4- to 6-membered heterocyclic group containing 1. to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, which may be substituted, and (b) with one or more other substituents, and the substituent options are described above.

It is particularly preferred herein that the substituent substituents are 1 to 4 substituents selected from (1) a halogen atom, (2) an oxo group, (3) a hydroxy group, (4) an optionally substituted C 1-4 alkyl group. , (5) a C1-10 alkoxy group, which may be substituted, (6) a C1-10 alkylsulfonyl group, (7) a morpholin-4-yl sulfonyl group, (8) a cyano group, (9) a carbamoyl group, (10) halogen group We are an alkylsulfonyloxy group,

54504 Β1 (11) some C3-7 cycloalkyl-C2-6 alkynyl group, (12) some di-C1-10 alkyl-amino group, (13) some mono- (C1-10 alkyl-carbonyl) -amino group, (14 ) a C1-10 alkoxycarbonyl group, (15) a phenoxy group, (16) a C1-10 alkylsulfinyl group, (17) a benzimidazol-2-yloxy group, ί (18) a benzimidazol-2-yl sulfonyl group .

[Compound (I0-F)]

In the compound described above (I0-E), are

R¹ represents a phenyl group, which may be substituted,

R² represents a halogen atom, a hydroxy group, a C1-10 alkyl group which may be substituted, or a C 1-10 alkoxy group which may be substituted, R³ represents a hydrogen atom, or a C1-10 alkoxy group, which may be substituted,

Ring A represents a benzene ring substituted with one substituent selected from (1) a C3-7 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 more substituents, and

Ring B represents an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an isoxazole ring, a 1,3-oxazole ring, a furan ring, or a thiophene ring, each of which may be substituted.

Here, as a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, for example, a morpholino group, a pyrrolyl group, a dihydropyrolyl group, a pyrazolyl group, a dihydropyrazolyl group are preferred. a group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group

54504 A Β1 group, an oxazolidinyl group, an imidazolyl group, an imidazolidinyl group, an isoxazolyl group, a pyridyl group, a piperazinyl group, or a thiazolyl group, wherein the substituent options are described above.

[Compound (10-G)]

In Compound (10-E), or in Compound (10-F), are

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

R² represents a C1-10 alkoxy group,

R³ represents a hydrogen atom,

Ring A represents 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 may be substituted by 1 to 4 substituents selected from atoms some halogen, some hydroxy groups, some oxo groups, halogen We are alkoxy groups, some C1-10 alkoxycarbonyl and some C1-10 alkyl groups which may be substituted by halogen and which may be substituted by 1 or 2 more substituents selected from a halogen atom and a C1-10 alkoxy group, and

Ring B represents a pyrazole ring.

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

In another aspect of the present invention, the following compounds, i.e., compounds (10-H) and (10-H) are preferred as compound (Io).

[Compound (I0-H)]

In Unity (lo), are

54504 Β1

R¹ represents 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 falling within the scope of the definition of a substituent Group A, as described above, which may be substituted ,,

R² represents a hydroxy group, a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted,

R³ represents a hydrogen atom or a C1-10 alkyl group, which may be substituted,

Ring A represents a 5- or 6-membered aromatic ring, which may be substituted with one or more substituents selected from a halogen atom, a cyano group, a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, carbamoyl groups, alkylsulfanyl groups which may be substituted, alkylsulfinyl groups which may be substituted, heterocyclic-sulfonyl groups, amino groups which may be substituted, cycloalkyl groups and saturated heterocyclic groups and Ring B represents a 5-membered aromatic heterocyclic ring, which may be substituted, the substituent options being described above.

[Compound (lo-l)]

In the Union (io), are

Ring A is a 5- to 6-membered aromatic ring (e.g. phenyl, pyridyl), which may be substituted with one or more substituents selected from (a) halogen atoms (e.g. chlorine, fluorine, iodine) (b) cyano group (c) C1-10 alkyl group, which may be substituted by 1 to 3 halogen atoms (eg methyl, trifluoromethyl), (d) C3-7 cycloalkyl group (eg methyl, trifluoromethyl), (e) C1- 10 alkoxy groups, which may be substituted by 1 to 3 halogen atoms (e.g. difluoromethoxy, methoxy), (f) a 5- to 10-membered heterocyclic group containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur (e.g. morpholinyl, benzimidazolyl, piperidinyl), (g) C1-10 alkyl- sulfonyl group (e.g. methylsulfonyl) (h) a 5- to 10-membered heterocyclic-sulfonyl group containing 1 to χ hetero atoms selected from nitrogen, oxygen and sulfur (e.g. morpholinylsulfonyl),

54504 Β1 (i) carbamoyl group,

R 1 represents (a) a C 1-10 alkyl group (e.g. isopropyl, isobutyl), or (b) a halogen atom (e.g. chlorine, fluorine), a C 1-10 alkyl group (e.g. methyl) a C 1-10 alkoxy group. methoxy),

R² represents (a) a hydroxy group (b) a C 1-10 alkyl group (e.g. methyl), or (c) a Smo alkoxy group, which may be substituted by one or more substituents selected from a halogen atom and a C 3-7 cycloalkyl group ( methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, difluoromethoxy),

R³ represents hydrogen, or a C1-10 alkyl group (e.g. methyl),

Ring B is preferably a 5-membered aromatic nitrogen-containing heterocyclic ring having 1 to 3 nitrogen atoms (e.g. pyrazole, triazole, tetrazole). and which may be substituted by a C1-10 alkyl group (e.g. methyl).

When the compound (s) 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 are included. Preferred examples of metal salts are, for example, alkali metal salts, such as sodium salts, potassium salts; alkaline earth metal, such as calcium salts, magnesium salts, barium salts; and aluminum salts. Preferred examples of salts with organic bases are salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylenediamine. Preferred examples of salts with inorganic acids are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid. Preferred examples of salts with organic acids are salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, citric acid, malic acid, methanesulfonic acid toluenesulfonic acid. Preferred examples of salts with basic amino acids are salts with arginine, lysine, ornithine. Preferred examples of salts with acidic amino acids are salts with aspartic acid, glutamic

54504 Β1 acid. Among them, pharmacologically acceptable salts are preferred. For example, in the case where an acidic functional group is present in the compound, for example, an inorganic salt, 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. salt. Conversely, in the case where 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 an organic acid, such as is acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, amber acid, methanesulfonic acid, ptoluensulfonic acid.

If the compound (lo) comprises isomers, such as tautomers, optical isomers, sterile isomers, reverse isomers and a rotational isomer, one of the isomers or mixtures of isomers is also included in the compound of the present invention. Further, compound (lo) has an optical isomer, this optical isomer, isolated from the racemate, is encompassed by the compound to).

Compound (lo) can be obtained in crystalline form. A single crystal form or mixture of crystals may be included in compound (lo).

The compound of formula (Io) may represent a pharmaceutically acceptable co-crystal or cocrystalline salt. The term co-crystal or co-crystalline salt, as used herein, means a crystalline material consisting of two or more unique solids at room temperature, each of which has inherent physical characteristics, such as structure, melting point and heat. melting, hygroscopicity, solubility and stability. Some co-crystal or baking co-crystal salt can be obtained according to some of the known co-crystallization methods.

Compound (lo) can be obtained as a solvate (e.g., hydrate) or as a non-solvate, and these are included in compound (lo).

Isotope-labeled compounds (e.g. ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, ¹²⁵l) are also encompassed by compound (lo).

54504 Β1 [Production methods]

The compound of the present invention, and this compound as a raw material, can be prepared in known ways, for example, by the methods shown in the schemes that follow. In the following, room temperature indicates a temperature that is usually in the range of 0 ° to 35 ° C, and low temperature usually indicates a temperature between -78 and 0 ° C.

Compound (lo) can be obtained, for example, by the process explained below or by a process comparable thereto. The process for the production of compound (lo) is explained below, in explaining the processes for the preparation of compounds (le), (lf), (lh), (li) and (lj) included in compound (lo). Methods for preparing compounds (Ia), (Ib), (ic), (Id) and (Ig) are given for comparison purposes.

The symbols used for the compounds in these reaction schemes have the same meanings mentioned above. In this application, the methyl group (SN2) is sometimes abbreviated Me. The compounds in these schemes may also include their salts, in the case where salts can be formed, and these salts are similar to the salts of the compounds (l_o). Further, the compound obtained in each of the processes can be used in subsequent reactions directly in the form of a reaction mixture, or as a crude product. However, it can be isolated from the reaction mixture according to a conventional method. The product itself can be easily purified by some known means of isolation, such as extraction, concentration, neutralization, filtration, distillation, recrystallization and chromatography. Alternatively, if a compound is commercially available in these schemes, the commercial product may be used directly, and in addition, those produced by known methods or methods comparable thereto may be used. If such a compound, as a raw material, contains an amino, carboxy, hydroxy or heterocyclic group, this group can be protected with a protecting group, which is commonly used in peptide chemistry. In this case, if desired, the target compound can be obtained by removing this 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, 3rd Edition (by Theodora W. Greene, Peter GM Wuts, published in 1999 in Wiley-lnterscience Corporation).

54504 Β1

Examples Χ · include halogen anions (e.g. chlorine anion, bromine anion, iodine anion), nitrate ion and phosphate ion.

In these production processes, the conversions of the substituent, each of the substituents in R¹ to R⁹ and each of the substituents in Rings A ΐ B, can be performed according to known methods, for example, by a method described in Comprehensive Organic Transformations (by Richard C. Larock, published 1999, in Wiley-VCH).

The following processes and processes may be performed without a solvent, or the crude materials may be dissolved or suspended in a suitable solvent, prior to the start of the reaction. In this case, one type of solvent may be used independently or two or more solvents may be combined in an appropriate ratio. Specific examples of the solvent to be used in the manufacturing processes of the present invention are provided specifically, as follows:

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, hexamethylphosphorus triamide.

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

Nitriles: acetonitrile, propionitrile.

Sulfoxides: dimethylsulfoxide.

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.

54504 Β1

Specific examples of bases or deoxidants used in the manufacturing processes of the compounds of this invention are given as follows:

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

Organic bases: triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, Nmethylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [0.0] none 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole.

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

Alkali metal hydrides: sodium hydride, potassium hydride.

Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide.

Organic lithium reagents: methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium.

Specific examples of acids or acid catalysts used in the production processes of the compounds of this invention are given as follows:

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, amber acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid.

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

When there is a leaving group in the coupling of heterocyclic compounds, carbamate compounds, acetylene derivatives, boric acid derivatives, or organotin compounds to Ring A, the product can be obtained by a coupling reaction, in the presence of a base, using both a palladium catalyst and a copper catalyst. or just one of them. "Heterocyclic compounds include imidazole ring compounds, pyrazole rings, pyrrolidine rings, azetidine rings,

54504 Β1 a pyrrolidone ring compound, a piperidone ring compound. "Carbamate compounds are oxazolidone ring compounds," acetylene derivatives are cyclopropylacetylene, "boric acid derivatives are (1-methyl-1H-pyrazol-4-yl) boric acid pinacol esters," organotin compounds are 2- (tributylstannyl) -1 , 3-oxazole.

As a palladium catalyst, for example, tris (dibenzylideneacetone) dipalladium (0), tetrakistriphenylphosphinepalladium (O) can be used. This palladium catalyst can be used in an amount ranging from about 0.01 to 1 mol, and preferably from 0.05 to 0.2 mol, relative to 1 mol of the reaction substrate. "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 mol, and preferably from 0.05 to 1 mol, relative to 1 mol of the reaction substrate. As a "phosphine ligand, for example, a phosphine ligand can be used, such as, for example, triphenylphosphine and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene. As copper catalyst, for example, cuprous iodide (Cul) and copper oxide (C112O) can be used. The copper catalyst can be used in an amount ranging from about 0.1 to 1 mol, and preferably from 0.1 to 0.5 mol, relative to 1 mol of the reaction substrate. In addition, “the copper catalyst can be used in conjunction 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 mol, and preferably from 0.1 to 2 mol, relative to 1 mol of the reaction substrate. As a base, sodium tert-butoxide or potassium phosphate can be used, and the amount ranges from about 1 to 10 mol, preferably from 1 to * mol, relative to 1 mol of the reaction substrate. Preferably, this reaction is carried out in the absence of a solvent or in the presence of an inert solvent for this reaction. The solvent used is not special limited if the reaction takes place, but for example, ethers and nitriles are preferred. Preferably, this reaction is usually carried out at room temperature or with heating, under reflux, and preferably under reflux with heating. The reaction time usually ranges from 0.5 to 48 h, preferably from 1 to 24 h.

The coupling reaction can be performed by the methods described in Cross-Coupling Reactions: A Practical Guide (Topics in Current Chemistry) (Springer) Experimental Organic Metallic Chemistry for Synthesizing Chemists (Kodansha) and in Organic Synthesis using Transition Metals (Kagaku Dojin) or some similar procedures.

54504 Β1

Compounds (le), (lf), (lh), (li) and (lj), each of which is contained in compound (lo), can be obtained according to production process E, production process F, production process H, production process by process I or production process J, as will be explained below. Compounds (Ia), (Ib), (Ic), (Id) and (Ig) and production methods A, B, C, D and G are given for comparison purposes.

The symbols in each general formula in the reaction schemes have the same meanings as mentioned above, unless otherwise specifically stated.

[Production Process A]

<img file="RS54504B1_D0005.tif" />

(II) (1: 1)

<img file="RS54504B1_D0006.tif" />

(IV)

Process 3

<img file="RS54504B1_D0007.tif" />

(VI)

<img file="RS54504B1_D0008.tif" />

[Production Process B]

N₃* X (f) · "AL".

<img file="RS54504B1_D0009.tif" />

(IX)

<img file="RS54504B1_D0010.tif" />

| H) (111) (VHI)

<img file="RS54504B1_D0011.tif" />

(XI) («» [Production Procedure C]

54504 Β1

<img file="RS54504B1_D0012.tif" />

(X) (XIII) £ XIV) (lc) [Production Procedure D]

<img file="RS54504B1_D0013.tif" />

SH) W {KVI?

[Production process E]

<img file="RS54504B1_D0014.tif" />

(III) (XVII) (XVIII) (XIX)

<img file="RS54504B1_D0015.tif" />

(XX) (XXI) (HHN)

<img file="RS54504B1_D0016.tif" />

[Production process F]

<td>ο о b</td><td>κνΑγ-ΜΗι Processl «11 J. Rp »ss« 16 - Θ</td><td>f </td><td>R¹</td><td>Pmcsttie v_w-^N R '</td>

<td>(XX)</td><td>(XXIV)</td><td>(XXV)</td><td>(XXVI}</td><td>(I)</td>

54504 Β1 [Production process G]

<td>t4₅'X'</td><td></td><td colspan="2">JULY. jh. Rgoiig ^M ρ ™ »« !? £ K</td>

<td>ό</td><td></td><td>ό</td><td>° JL φ</td>

<td>(VD</td><td>(XXVII)</td><td>(XXVIin</td><td>(XXIX)</td>

<td>ProGess' 8</td><td colspan="2"> ......</td><td>OMe Ο HJChmv M «</td>

<td></td><td> 0</td><td> 0</td><td> 0</td>

<td></td><td>(XXXI</td><td>(XXXI)</td><td>(XXX il)</td>

<td> 13</td><td>OMeO / X r ^ z</td><td>XVv ·· . ⁰ ϊ! + R'NHNHz</td><td>X # Rgoagaz * a ' ---------- s- NX</td>

<td> --------------</td><td>sgu ...... ♦ Θ</td><td>)Α) &lt;VM&gt;</td><td> ©</td>

<td></td><td>(ХХХШ)</td><td>(XXXIV)</td><td>(XXXV)</td>

<td>Procew19</td><td colspan="2"></td><td></td>

<td></td><td>ό</td><td> 0</td><td></td>

<td></td><td>ooani)</td><td></td><td></td>

[Production process H]

<img file="RS54504B1_D0017.tif" />

[Production Process I]

<img file="RS54504B1_D0018.tif" />

(XXIV&gt;

<img file="RS54504B1_D0019.tif" />

<img file="RS54504B1_D0020.tif" />

<img file="RS54504B1_D0021.tif" />

54504 Β1 [Production process J]

<img file="RS54504B1_D0022.tif" />

Process 1 is a process for preparing compound (III), by reacting compound (II) with a diazotizing agent. If desired, this reaction can be performed in the presence of an acid.

Examples of diazotizing agents are as follows: alkali metal nitrites, such as sodium nitrite and potassium nitrite; Sg-β alkyl esters of nitric acid, such as t-butyl nitrite and isoamyl nitrite; nitrosyl chloride, nitrosyl sulfate and nitric oxide. Among them, sodium nitrite is desirable, because it is easily available and has a low price. Furthermore, nitric acid alkyl esters are preferred because they improve reactivity. In this case, thanks to the fact that the alkali metal nitrite is solid at room temperature, it dissolves in water before use.

As "acid", for example, hydrochloric acid, sulfuric acid and acetic acid are useful, and they can also be used in the mixture,

From the standpoint of increased reactivity and economic efficiency, the amount of diazotizing reagent ranges from 1 to 5 mol and preferably from 1 to 2 mol, relative to 1 mol of compound (II). Preferably this reaction is carried out at room temperature or at a lower temperature, and preferably the temperature ranges from -30 ° C to 0 ° C.

Typically, the reaction time ranges from 1 min to χ h, preferably from 1 min to 1 h.

Preferably this reaction is carried out in the absence of a solvent or in the presence of an inert solvent in this reaction. These solvents are not limited as long as the reaction proceeds, but water is preferred.

54504 Β1

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

This process can be performed by the method described in Tetrahedron Lett., 2008, 49 (14), 2262-2264 or some similar method. If desired, this reaction can be performed in the presence of a base.

The amount of compound (IV), (VIII), (XVII) or (XXVII) to be used ranges from approximately 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of compound (III).

As the base, for example, sodium acetate can be used.

The amount of "base" to be used typically ranges from 1 to 10 equivalents, preferably from 2 to 6 equivalents, relative to compound (III).

Preferably this reaction is carried out in the absence of a solvent or in the presence of an inert solvent in this reaction. There are no restrictions on these solvents, as long as the reaction proceeds, but a mixed solvent, alcohol and water are preferred.

Preferably, this reaction is usually carried out at room temperature or at some low temperature, with cooling in an ice bath.

Usually the reaction time ranges from 5 s to 24 h, and preferably from 5 s to 1 h.

R⁴ is a C 1-10 alkyl group, which may be substituted, and a methyl group or ethyl group is preferred. In this process, R² represents a C1-10 alkyl group, which may be substituted, or a C1-10 alkoxy group, which may be substituted, wherein the substituent options are described above.

Process h is a process for preparing compound (VI), compound (X), compound (XIX), compound (XXIII) or compound (XXXIV), from compound (V), compound (IX), compound (XVIII), compound (XXII). ) or compounds (XXXIII). This reaction can be performed in the presence of N, N-dimethylfornamide and dimethylacetal as solvents.

54504 Β1

This process can be performed by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a process similar to it.

Preferably this reaction is usually carried out under reflux, with heating, preferably at 100 ° C to 150 ° C.

Usually the reaction time ranges from 1 to 10 hours, preferably from 1 to 5 hours.

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

The amount of compound (VII) to be used ranges from about 1 to 10 mol, preferably from about 2 to 5 mol, relative to 1 mol of compound (VI), compound (XXIII) or compound (XXXIV).

Preferably, this reaction is carried out in the absence of a solvent or in the presence of a solvent which is inert in this reaction. There are no restrictions on the solvent to be used, as long as the reaction proceeds, but alcohols, organic acids or mixtures of these solvents are preferred.

Preferably this reaction is usually carried out in an ice bath, at room temperature, or under reflux, with heating, and preferably at 0 ° C to 150 ° C.

Typically, the reaction time ranges from 0.1 to 10 h, preferably from 0.5 to 5 h.

This process can be performed by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a process similar to it.

In this process, R¹ represents a C1-10 alkyl group, which may be substituted, a C3-10 cycloalkyl group, which may be substituted, or an aromatic group, which belong to the definitions of a substituent in the Substituent Group A, as described above, which may be substituted , wherein the substituent options are described above.

54504 Β1

Process 5 is a process for the preparation of compound (XI), by reacting compound (X) with hydrazine, a process for preparing compound (XIII), reacting compound (X) with ammonia, or a process for preparing compound (XV), by reacting compound (X) with some by amine compound (XII).

The amount of hydrazine, ammonia and amine compound (XII) to be used ranges from about 1 to 10 mol, preferably from about 2 to 5 mol, relative to 1 mol of compound (X).

Preferably this reaction is carried out in the absence of a solvent or in the presence of an inert solvent in this reaction. There are no restrictions on the solvent as long as the reaction proceeds, but for example, alcohols or ethers are preferred.

Preferably, this reaction is usually carried out under heating conditions, preferably at 50 ° C to 100 ° C.

Usually the reaction time ranges from 1 to 10 hours, preferably from 1 to 5 hours.

This process can be performed by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a process similar to it.

Furthermore, it is convenient to use a heating process under microwave conditions or a heating process in the presence of trimethyl-aluminum as an activator.

The reaction temperature, in the case where microwave heating is used, usually ranges from 50 ° C to 150 ° C, preferably from 100 ° C to 130 ° C. Usually the reaction time ranges from 10 to 60 minutes, preferably from 10 to 20 minutes. Preferably this reaction is carried out in the absence of a solvent or using a solvent which is inert in this reaction. The solvent is not limited as long as the reaction proceeds, but for example, alcohols or ethers are preferred.

If the reaction is performed in the presence of trimethyl aluminum as an activator, trimethyl aluminum is used in an amount ranging from about 1 to 5 mol, preferably from about 1 to χ mol, relative to 1 mol of compound (X). It is convenient to perform this reaction

54504 Β1 in the absence of a solvent or to use a solvent that is inert in this reaction. The solvent is not limited as long as the reaction proceeds, but methylene chloride is preferred. Preferably, this reaction is usually carried out under heating conditions, preferably at 50 ° to 100 ° C. Usually the reaction time ranges from 1 to 15 h, preferably from 1 to 10 h.

Process 6 is a process for preparing compound (1b) by placing compound (XI) together with an amine compound (XII).

In the case when R⁵ represents hydrogen, compound (XI) is reacted with N, N-dimethylformamide - dimethylacetal or the like, and then reacted with some amine compound (XII), under acidic conditions, without isolation, to give compound (1b). Contrary to this, if R⁵ represents a methyl group, compound (XI) is reacted with N, N-dimethylacetamide - dimethylacetal, and the reaction is carried out with an amine compound (XII), under acidic conditions, as mentioned above, to give compound (1b).

The amount of N, N-dimethylformamide-dimethylacetal or N, N-dimethylacetamide-dimethylacetal used ranges from about 1 to 5 mol, preferably from about 1 to 2 mol, relative to 1 mol of compound (XI).

Preferably, this reaction is usually carried out under heating conditions, preferably at 50 ° to 100 ° C.

Usually the reaction time ranges from 0.5 to χ h, preferably from 0.5 to 1 h.

Preferably, this reaction is carried out in the absence of a solvent or using a solvent which is inert in this reaction. The solvent is not limited as long as the reaction proceeds, but for example, nitriles are preferred.

The amount of amine compound (XII) to be used ranges from 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of compound (XI).

As "acid", for example, acetic acid can be used.

54504 Β1

The amount of acid to be used, it is preferable to use the same amount of solvent as the acetonitrile in the above reaction.

Preferably this reaction is carried out under heating conditions, preferably from 100 ° C to 130 ° C.

Usually the reaction time ranges from 0.5 to χ h, preferably from 0.5 to 1 h.

This process can be performed by the procedure described in Org. Lett, 2004, 6 (17), 2969-2971 or with some similar procedure.

Process 7 is a process for preparing compound (XIV) from compound (XIII). This product can be obtained in the presence of N, N-dimethylformamide dimethylacetal as a solvent.

Preferably this reaction is carried out under heating conditions, preferably at 100 ° C to 150 ° C.

Usually the reaction time ranges from 0.1 to 5 h, preferably from 0.1 to 1 h.

This process can be performed by the procedure described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 or with some similar procedure.

Process 8 is a process for preparing compound (lc) by placing compound (XIV) together with a hydrazine compound (VII). This reaction can be performed in the presence of an organic acid.

The amount of hydrazine (VII) compound to be used ranges from 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of compound (XIV).

As "organic acid", for example, acetic acid can be used.

The amount of this organic acid to be used is similar to the amount usually used as a solvent.

54504 Β1

Preferably this reaction is carried out under heating conditions, preferably at 100 ° C to 130 ° C.

Usually the reaction time ranges from 0.5 to * h, preferably from 0.5 to 1 h.

This process can be performed by the procedure described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 or with some similar procedure.

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

Preferably, this reaction is carried out in the absence of a solvent or a solvent which is inert in this reaction. There are no particular restrictions on the solvent as long as the reaction proceeds, but halogenated hydrocarbons, for example, are preferred.

The amount of 1H-benzo [d] [1,2,3] triazole to be used ranges from 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound (XV).

As the "acid halide", for example, thionyl chloride can be used.

The amount of acid halide to be used ranges from about 1 to 5 equivalents, preferably from 1 to 2 equivalents, relative to compound (XV).

Preferably, this reaction is performed under reflux, with heating, and it is also possible for this reaction to be performed in a short time under microwave conditions. If this reaction is carried out under microwave conditions, with 80 watts, the reaction time ranges from 0.1 to 1 h, preferably from 0.1 to 0.3 h.

This process can be performed by the method described in Synthesis, 2007, 1204-1208 or by a process similar to it.

54504 Β1

Process 10 is a process for preparing compound (1d) from compound (XVI). This product can be obtained by reacting an acid, as well as sodium azide, in the presence of a phase transfer catalyst.

Preferably, this reaction is performed using a solvent that is inert in this reaction. There is no particular limitation on this solvent as long as the reaction proceeds, but for example, it is useful to use a halogenated hydrocarbon in a mixture with water as the solvent.

Tetrabutyl ammonium bromine can be used as a "phase transfer catalyst", for example.

The amount of "phase transfer catalyst" to be used ranges from 0.1 to 1 equivalent, preferably 0.1 to 0.3 equivalent, relative to compound (XVI).

The amount of sodium azide to be used ranges from about 1 to 5 mol, preferably from 1 to x mol, relative to 1 mol of compound (XVI).

Organic acids, for example, can be used as the acid.

The amount of "acid" to be used ranges from about 1 to 5 equivalents, preferably from 1 to 2 equivalents, relative to compound (XVI).

The reaction temperature ranges from 0 ° C to 100 ° C, preferably at room temperature.

Usually the reaction time ranges from 1 to 48 hours, preferably from 10 to 24 hours.

This process can be performed by the method described in Synthesis, 2007, 1204-1208 or by a process similar to it.

Process 11 is a process for preparing compound (XX) or compound (XXXI) from compound (XIX) or compound (XXX). This reaction can be performed under acidic or basic conditions. Preferably, this reaction is carried out without the use of solvent III of a solvent which is inert in this reaction. Solvent to be used

54504 Β1 is not particularly limited as long as the reaction proceeds, but it is preferred, for example, to use alcohols mixed with water and ethers as solvent.

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

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

The amount of this acid or base to be used ranges from about 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound (XIX) or compound (XXX).

Preferably this reaction is usually carried out at room temperature or with heating, and preferably at room temperature.

Usually the reaction time ranges from 1 to 48 h, preferably from χ to 10 h.

Process 12 is a process for preparing compound (XXI) or compound (XXXII) from compound (XX) or compound (XXXI). This product can be obtained using N, O-dimethylhydroxylamine hydrogen chloride, with a condensing agent, in the presence of a base, such as triethylamine or N, N-diisopropylethylamine. Alternatively, the carboxylic acid of the substrate is converted to the corresponding acid halide, which is then reacted with NO-dimethylhydroxylamine hydrogen chloride to give the target products.

As the condensing agent, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrogen chloride can be used in the presence of 1-hydroxybenzotriazole.

Preferably this reaction is carried out without the use of a solvent or in the presence of a solvent which is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, and nitriles, ethers and amides are preferred, for example.

The amount of condensing agent to be used ranges from about 1 to 5 mol, preferably 1 to * mol, relative to 1 mol of compound (XX) or compound (XXXI).

54504 Β1

Preferably, the base, such as triethylamine or N, N-diisopropylethylamine, is used in an amount ranging from 1 to 10 mol, preferably from 2 to * mol, relative to 1 mol of compound (XX) or compound (XXXI). ).

Preferably this reaction is usually carried out at room temperature or with heating, and preferably at room temperature.

Usually the reaction time ranges from 1 to 48 h, preferably from 5 to 10 h.

This reaction with an acid halide is performed in the presence of a base, such as triethylamine, using N, N-dimethylhydroxylamine hydrogen chloride to synthesize the target product.

Preferably, this reaction is performed without the use of a solvent or a solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but ethers, esters, amides are preferred, for example.

The amount of base, such as triethylamine, ranges from about 1 to 10 mol, preferably from 2 to * mol, relative to 1 mol of compound (XX) or compound (XXXI).

Preferably this reaction is carried out with cooling, in an ice bath or at room temperature, and preferably with cooling in an ice bath.

Usually the reaction time ranges from 0.5 to 5 h, preferably from 1 to χ h.

In addition, compound (XXI) or compound (XXXII) can be obtained by reacting compound (XIX) or compound (XXX) with trimethyl aluminum and N, Odimethylhydroxylamine hydrogen chloride, in the presence of an organic base. The amount of organic base, trimethyl aluminum and N, N-dimethylhydroxylamine hydrogen chloride ranges from about 1 to 10 mol, preferably from 2 to 5 mol, relative to 1 mol of compound (XIX) or compound (XXX). Preferably this reaction is carried out without the use of a solvent, or in the presence of a solvent which is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but halogenated hydrocarbons are preferred, for example. Preferably, this reaction is usually performed with

54504 Β1 cooling in an ice bath or at room temperature, preferably with cooling in an ice bath. Usually the reaction time ranges from 1 to 24 h, preferably from 1 to 5 h.

Process 13 is a process for preparing compound (XXII) or compound (XXXIII) from compound (XXI) or compound (XXXII). The product can be obtained using an acylating agent, such as a Grignard reagent or a lithium organic reagent.

Preferably, this reaction is performed without the use of a solvent or a solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but ethers are preferred, for example.

The amount of "alkylating agent" ranges from about 1 to 10 mol, preferably from 2 to χ mol, relative to 1 mol of compound (XXI) or compound (XXXII).

Preferably this reaction is usually carried out at -78 ° C or with cooling in an ice bath, but is preferably at -78 ° C.

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.

R⁸ and a hydrogen atom, or a C1-10 alkyl group, which may be substituted as described above, and preferably a hydrogen atom, a III methyl group.

Usually the reaction time ranges from 1 to 10 h, preferably from 1 to χ h.

Process 14 is a process for preparing compound (XXIV) from compound (XX). This product can be obtained using diphenylphosphoryl azide, in the presence of a base, such as triethylamine.

Preferably, this reaction is performed without the use of a solvent, or using a solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds. For example, when used

54504 Β1 tert-butanol as solvent, a tert-butyl carbamate derivative was obtained temporarily, and its hydrolysis was carried out under acidic conditions to give compound (XXIV). In addition, in the case where toluene is used as the solvent, then the isocyanate as the intermediate is hydrolyzed in aqueous sodium hydroxide solution to give compounds (XXIV).

The amount of diphenylphosphoryl azide ranges from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XX).

The amount of triethylamine ranges from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XX).

Preferably this reaction is usually carried out at room temperature or under reflux, with heating, and preferably under reflux with heating.

Usually the reaction time ranges from 1 to 20 h, preferably from 1 to 10 h.

This process can be performed by the method described in Tetrahedron 1974, 30, 2151-2157 or by some similar method.

Process 15 is a process for preparing compound (XXV) from compound (XXIV). This product can be obtained using some nitrite, in the presence of some copper salt.

Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but amides, for example, are preferred.

As the copper salt, cuprous bromide (SiVgg) can be used, and its amount ranges from about 1 to 5 mol, preferably from 1 to 2 mol, relative to 1 mol of compound (XXIV).

As nitrite, isoamyl nitrite or pentyl nitrite can be used, and its amount ranges from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XXIV).

54504 Β1

Preferably, this reaction is usually carried out in an ice bath, at room temperature or with heating, and the temperature is preferably in the range of 0 ° to 70 ° C.

Usually the reaction time ranges from 1 to 10 hours, preferably from 1 to 5 hours.

This process can be performed by the method described in US5059599 or by a process similar to it.

Process 16 is a process for preparing compound (lf) from compound (XXV) and compound (XXVI). This product can be obtained using a palladium catalyst, in the presence of a base.

The amount of compound (XXVI) to be used ranges from about 1 to 10 mol, preferably from about 1 to χ mol, relative to 1 mol of compound (XXV).

As a base, potassium acetate or potassium carbonate can be used, and its amount ranges from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XXV).

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

Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but is preferred, for example, alcohols, a mixture of solvent and water, aromatic hydrocarbons, ethers, amides.

Preferably this reaction is usually carried out at room temperature or under reflux, with heating, and preferably under reflux, with heating.

Usually the reaction time ranges from 5 to 48 h, preferably from 10 to 20 h.

54504 Β1

This process can be performed by the procedure described in Org. Lett., 2006, 8, 17871789 or with some similar procedure.

R⁹ represents an alkoxy group, which may be substituted or a hydroxyl group.

Process 17 is a process for preparing compound (XXIX) from compound (XXVIII), and this reaction can be performed in the presence of a base.

As the base, base salts, organic bases, metal alkoxides or metal amides can be used, with potassium carbonate or sodium methoxide being preferred. The amount of this base ranges from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XXVIII). Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but ethers or amides, for example, are preferred. Preferably this reaction is usually carried out at room temperature or under reflux, with heating, and preferably at room temperature.

The reaction time usually ranges from 1 to 24 hours, preferably from 2 to 4 hours.

Process 18 is a process for preparing compound (XXX) or compound (Ig) from compound (XXIX) or compound (XXXVI).

Methylation can be performed under conditions used with trimethylsilyldiazomethane or methyl iodide in the presence of a base.

In the case where the reaction is performed using trimethylsilyldiazomethane, trimethylsilyldiazomethane is used in an amount ranging from 10 to 50 mol, preferably 5 to 20 mol, relative to 1 mol of compound (XXIX) or compound (XXXVI), using methanol as solvent. Preferably, this reaction is usually carried out with cooling in an ice bath or at room temperature, and preferably with cooling in an ice bath.

54504 Β1

Usually the reaction time ranges from 1 to 5 h, preferably from 1 to 2 h.

In the case where methyl iodide is used, in the presence of a base, this reaction can be carried out using ether as a solvent, in the presence of sodium hydroxide.

Methyl iodide is used in an amount ranging from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol 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 mol, preferably from 1 to * mol, relative to 1 mol of compound (XXIX) or compound (XXXVI). Preferably, this reaction is carried out usually by cooling in an ice bath or at room temperature, and preferably by cooling in an ice bath.

Usually the reaction time ranges from 1 to 5 h, preferably from 1 to 2 h.

Process 19 is a process for preparing compound (XXXVI) from compound (XXXV), and this product can be obtained from trimethylsilyl chloride, in the presence of sodium iodide.

The amount of sodium iodide ranges from about 1 to 10 mol, preferably from 1 to 5 mol, relative to 1 mol of compound (XXXV). The amount of trimethylsilyl chloride ranges from about 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound (XXXV).

Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but nitriles, for example, are preferred. Preferably this reaction is usually carried out at room temperature or under reflux, with heating, preferably under reflux, with heating. Usually the reaction time ranges from 1 to 20 h, preferably from χ to 10 h.

Process 20 is a process for the preparation of compound (XXXVII) from compound (XIX), and this product can be obtained using a suitable reducing agent.

As a reducing agent, lithium aluminum hydride, diisobutylaluminum hydride can be used. It can be used in an amount ranging from about 1 to 10 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XIX). It is convenient to

54504 Β1 this reaction is carried out without the use of any solvent, or any solvent which is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but ethers are preferred, for example. Preferably this reaction is usually carried out at -78 ° C or by cooling in an ice bath, and preferably at -78 ° C.

Usually the reaction time ranges from 0.5 to 5 h, preferably from 1 to * h.

This process can be performed by the procedure described in Comprehensive Organic Transformations (WILEYVCH) or by a process similar to it.

Process 21 is a process for preparing compound (XXXVIII) from compound (XXXVII), and this product can be obtained using the appropriate oxidation.

As “oxidation, one can use, for example, Swern oxidation, or oxidation using an oxidant, such as sulfur trioxide, pyridine complex, pyridinium chlorochromate. When oxidation is performed using an oxidant, the amount of oxidant used ranges from about 1 to 10 mol, preferably from 1 to * mol, relative to 1 mol of compound (XXXVII). Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but for example, dimethylsulfoxide, halogenated hydrocarbons, ethers and esters are preferred. Preferably, this reaction is usually carried out at low temperature or at room temperature. Usually the reaction time ranges from 1 to 10 h, preferably from 1 to * h.

This process can be performed by the method described in Comprehensive Organic Transformations (WILEYVCH) or in Oxidation in Organic Chemistry (American Chemical Society) by a comparable method.

Process 22 is a process for preparing compound (1h) from compound (XXXVIII). Using α-tosyl benzyl isocyanide (Organic Syntheses, Coll. Vol. 10, p692 (2004: Vol. 77, p. 198 (2000)), 1,3-oxazole or 1,3-imidazole compounds can be obtained. In case you get it^m compound 1,3-oxazole, the reaction is carried out in the presence of a base, such as potassium carbonate. Conversely, in the case where the 1,3-imidazole compound is obtained, the reaction is carried out in the presence of a base, such as

54504 Β1 potassium carbonate, together with the presence of ammonia gas or an amine, such as methylamine.

A base, such as potassium carbonate, ammonia gas or methylamine, is used in an amount ranging from about 1 to 10 mol, preferably from 1 to χ mol, relative to the compound (XXXVIII). Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but ethers, nitriles and amides are preferred, for example. Preferably this reaction is usually carried out at low temperature or at room temperature, and preferably at room temperature.

The reaction time usually ranges from 5 to 30 hours, preferably from 5 to 15 hours.

This process can be performed by the procedure described in “New Edition: Heterocyclic Compounds” (Kodansha) or by a similar procedure.

Process 23 is a process for preparing compound (l) from compound (XXIV). As long as the reaction proceeds, there are no particular limitations, but after reacting with a solution of glyoxal in water, in an alcoholic solvent, under acidic conditions, compound (XXIV) can react with ammonium chloride and benzaldehyde to give compound (s).

A solution of glyoxal in water is used in an amount ranging from about 1 to 5 mol, preferably from 1 to χ mol, relative to 1 mol of compound (XXIV). Preferably, this reaction is usually carried out at low temperature or at room temperature, and is preferably at room temperature.

The reaction time usually ranges from 5 to 30 hours, preferably from 10 to 20 hours.

Benzaidehydride and ammonium chloride are used in an amount ranging from about 1 to 5 mol, preferably from 1 to h mol, relative to 1 mol of compound (XXIV). The acid to be used is not particularly limited as long as the reaction proceeds, but, for example, phosphoric acid is preferred. Preferably, this reaction is performed in a room

54504 Β1 temperature or under reflux, with heating, and preferably under reflux, with heating. Typically, the reaction time ranges from 5 to 40 h, preferably from 20 to 30 h.

This process can be performed by the procedure described in “New Edition: Heterocyclic Compounds” (Kodansha) or by a similar procedure.

Process 24 is a process for preparing compound (XXXIX) from compound (XXV). As long as the reaction proceeds, it is not particularly limited, but this product can be obtained 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 palladium catalyst, for example, bis (triphenylphosphine) palladium (II) dichloride can be used. This palladium catalyst is used in an amount ranging from about 0.01 to 1 mol, preferably from 0.05 to 0.2 mol, relative to 1 mol of compound (XXV). In addition, this palladium catalyst is used in conjunction with a phosphine ligand, such as triphenylphosphine. This phosphine ligand is used in an amount ranging from about 0.01 to 1 mol, preferably from 0.05 to 0.2 mol, relative to 1 mol of compound (XXV). As a copper catalyst, for example, cuprous iodide (Cul) can be used. This copper catalyst is used in an amount ranging from about 0.1 to 1 mol, preferably from 0.1 to 0.5 mol, in a ratio of 1 mol of compound (XXV). Trimethylsilylacetylene is used in an amount ranging from about 1 to 5 mol, preferably from 1 to * mol, relative to 1 mol of compound (XXV). This reaction is carried out in the presence of a base such as triethylamine, and the amount of base to be used ranges from about 1 to 5 mol, preferably from 1 to * mol, relative to 1 mol of compound (XXV), Preferably is that this reaction is carried out by heating, at a temperature ranging from 40 to 60 ° C.

The reaction time usually ranges from 1 to 10 days, preferably from 5 to 7 days.

This process can be performed by the method described in Tetrahedron Lett, 1975, 16, 4467-4470 or by some similar procedure.

Process 25 is a process for preparing compound (XL) from compound (XXXIX). As long as the reaction proceeds, it is not particularly limited, but this product can be obtained by reacting compound (XXXIX) with an aqueous solution of sodium hydroxide or some

54504 Β1 of a fluoride ion, such as tetrabutylammonium fluoride, in an alcohol or ether as a solvent. The amount of aqueous sodium hydroxide solution or fluoride ions ranges from about 1 to 100 mol or more, preferably from 1 to χ mol, relative to 1 mol of compound (XXXIX). Preferably this reaction is carried out by cooling in an ice bath or at room temperature, preferably at room temperature. Usually the reaction time ranges from 0.5 to 5 h, preferably from 1 to χ h.

Process 26 is a process for preparing compound (I1) from compound (XL). As long as the reaction proceeds, it is not particularly limited, but this product can be obtained by reacting compound (XL) with N-hydroxybenzenecarboximidoyl chloride, in some ether, as a solvent. N-hydroxybenzenecarboxyimidoyl chloride is used in an amount ranging from about 1 to 5 mol, preferably from 1 to^x mol, relative to 1 mol of compound (XL). This reaction is carried out in the presence of a baking base, such as triethylamine, and the amount of base to be used ranges from about 1 to 5 mol, preferably from 1 to χ mol, relative to 1 mol of core (XL). Preferably this reaction is carried out by cooling in an ice bath at room temperature, and preferably at room temperature. Usually the reaction time ranges from 1 to 48 hours, preferably from 5 to 20 hours.

This process can be done by the procedure described in New Edition: Heterocyclic Compounds (Kodansha) or by a similar procedure.

Compound (le), in which R² represents a halogen atom (e.g. a bromine atom), can be obtained by the following procedure. First, compound (V) is reacted with a reagent, such as N, N-dimethylformamide-dimethylacetal, to give compound (XXII), wherein R² and R⁷ hydrogen atoms. The amount of reagent, such as N, N-dimethylformamide-dimethylacetal, is about 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of compound (V). Preferably, this reaction is performed using a solvent that is inert in this reaction (e.g., amides). Preferably this reaction is carried out at room temperature or with heating, and preferably the temperature ranges from 40 ° to 100 ° C. Usually the reaction time ranges from 1 to 20 h, preferably from 1 to 10 h. Then, this obtained compound (XXII) is reacted with a halogen molecule (e.g. bromine molecule) to bring a halogen atom to the R position² compounds (XXII). The amount of this halogen molecule to be used ranges from about 1 to 5 mol, preferably about 1 to 2 mol, relative to 1 mol of compound (XXII). It is desirable

54504 Β1 that this reaction is carried out using a solvent which is inert in this reaction (e.g. organic acids). It is preferred that this reaction be carried out at room temperature or at some low temperature, and preferably at room temperature. Usually the reaction time ranges from 1 to 10 h, preferably from 1 to χ h.

Compound (le), in which R⁸ represents a C1-10 alkyl group (e.g. a methyl group) can be obtained by the following procedure. First, compound (XXII) is reacted with a reagent, such as N, N-dimethylacetamide-dimethylacetal, to give compound (XXIII). The amount of N, N-dimethylacetamide-dimethylacetal to be used ranges from about 1 to 30 mol, preferably 5 to 20 mol, relative to 1 mol of compound (XXII). Preferably, this reaction is performed without the use of a solvent or a solvent that is inert in this reaction. In addition, it is desirable to carry out this reaction under reflux, with heating, but it is possible to heat under microwave conditions. The reaction temperature, when heating is performed under microwave conditions, ranges from 50 ° C to 150 ° C.₁ and preferably the temperature ranges from 100 ° C to 130 ° C. Typically, the reaction time ranges from 1 to 60 minutes, preferably from χ to 20 minutes.

Compound (le), in which R^s represents a C1-10 alkyl group, which is substituted by a fluorine atom (e.g. a trifluoromethyl group), can be obtained by the following procedure. First, compound (XXII) is reacted, under basic conditions, with an ester having an alkyl group substituted with a fluorine atom (e.g. ethyl trifluoroacetate). The amount of this ester to be used ranges from 1 to 20 mol, preferably 1 to 10 mol, relative to 1 mol of compound (XXII). This reaction is carried out in the presence of a base, such as sodium methoxide, and the amount of this base to be used ranges from about 1 to 5 mol, preferably from 1 to χ mol, relative to 1 mol of the compound (XXII ). Preferably this reaction is carried out using a solvent, which is inert in this reaction (e.g. ethers). Preferably this reaction is performed under cooling or at room temperature, and preferably at room temperature. Usually the reaction time ranges from 0.5 to 7 days, preferably from 1 to χ days. In addition, compound (Ie) can be obtained by placing the reaction product together with compound (VII). The amount of compound (VII) to be used ranges from about 1 to 10 mol, preferably from about 2 to 5 mol, relative to 1 mol of crude material. Preferably, this reaction is performed without the use of a solvent, or a solvent that is inert in this

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54504 Β1 reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but for example, alcohols and organic acids or solvent mixtures are preferred. Preferably this reaction is carried out with cooling, or at room temperature, or with heating, and preferably the temperature ranges from 0 ° C to 150 ° C. Typically, the reaction time ranges from 0.1 to 10 h, preferably from 0.5 to 5 h. This process can be performed by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333334 or by a process similar to it.

Compound (le), in which R⁷ represents a halogen atom (e.g. a fluorine atom) can be obtained by reacting a compound (le), in which R⁷ represents a hydrogen atom, with a reagent, such as a halogenating agent. For example, when a fluorine atom is to be introduced, 1- (chloromethyl) 4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (hereinafter referred to as Selectfluor) can be used as a fluorinating agent. . The amount of Selectfluor to be used ranges from about 1 to 30 mol, preferably 5 to 20 mol, relative to 1 mol of compound (le). Preferably, this reaction is performed using a solvent that is inert in this reaction (e.g., nitriles). In addition, this reaction is preferably carried out under ice-cooling or at room temperature, and preferably at room temperature. The reaction time usually ranges from 1 to 20 days, preferably from 5 to 15 days.

Compound (le), in which R⁷ represents a C1-10 alkyl group (e.g. methyl group), can be obtained by the following reaction. First, compound (XXII) is reacted with an ester (e.g. methyl formate), under basic conditions. This ester is also a solvent. This reaction is carried out in the presence of a base, such as sodium methoxide, and the amount of this base to be used ranges from about 1 to 5 mol, preferably from 1 to * mol, relative to 1 mol of the compound (XXII ). It is usually preferred that this reaction be carried out under ice-cooling, or at room temperature, and preferably at room temperature. Usually the reaction time ranges from 1 to 20 h, preferably from 2 to 10 h.

Compound (Ie) can be obtained by combining this reaction product with compound (VII). The amount of compound (VII) to be used ranges from about 1 to 10 mol, preferably from about 2 to 5 mol, relative to 1 mol of crude material. Preferably, this reaction is performed without the use of a solvent, or any solvent that is inert in this reaction. The solvent to be used is not particularly limited

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54504 Β1 as long as the reaction proceeds, but, for example, alcohols t organic acids or solvent mixtures are preferred. It is generally preferred that this reaction be carried out under ice-cooling, or at room temperature, or under reflux, with heating, and preferably ranging from 0 ° C to 150 ° C. Usually the reaction time ranges from 0.1 to 10 h, preferably from 0.5 to 5 h. This process can be performed by the method described in the Journal of Heterocyclic Chemistry, 1981, 18, 333-334 or by a process similar to it.

If the crude material of this compound contains as an substituent an amino group, a carboxyl group, a hydroxyl group, in each of the reactions of the process for the preparation of said compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (1x), (L) and (L), or their salts, and in each reaction of the synthesis of the crude material of these compounds, a protecting group, commonly used in peptide chemistry, may be introduced into this group. If desired, this protecting group is removed by a reaction that allows the target compound to be obtained.

As the protecting group for the amino group, for example, formyl can be used, and the following groups can be substituted respectively: C1-10 alkylcarbonyl (e.g. acetyl, ethylcarbonyl), phenylcarbonyl, C1-10 alkyl-oxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl) ), phenyloxycarbonyl, C7-10 aralkylcarbonyl (e.g. benzylcarbonyl), trityl, phthaloyl, or N, N-dimethylaminomethylene. Substituents to be used may be halogen (e.g. fluorine, chlorine, bromine, iodine), C1-10 alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, butylcarbonyl), nitro group. The number of substituents ranges from 1 to 3.

As the protecting group for the carboxyl group, for example, the following group can be used, which can be respectively substituted: C1-10 alkyl (eg methyl, ethyl, n-propyl, ipropyl, n-butyl, tert-butyl), phenyl , trityl, or silyl. Substituents to be used may be halogen (e.g. fluorine, chlorine, bromine, iodine), formyl, C1-10 alkylcarbonyl (e.g. acetyl, ethylcarbonyl, butylcarbonyl), nitro groups. The number of substituents ranges from 1 to 3.

As the protecting group for the hydroxyl group, for example, the following group can be used, which can be respectively substituted: C1-10 alkyl (eg methyl, ethyl, n-propyl, ipropyl, n-butyl, tert-butyl), phenyl , C7-10 aralkyl (e.g. benzyl), formyl, C1-10 alkylcarboxyl (e.g. acetyl, ethylcarbonyl), phenyloxycarbonyl, benzoyl, C7-10 aralkylcarbonyl (e.g. benzylcarbonyl), pyranyl, furanyl, or silyl. Substituents to be used may be

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54504 Β1 halogen (ex. Fluorine, chlorine, bromine, iodine), C1-10 alkyl (e.g. methyl, ethyl, 1-propyl), phenyl, C7-10 aralkyl (ex. Benzyl), nitro group. The number of substituents ranges from 1 to 4.

Further, as a process for deprotection, a known process or a similar process may be used. For example, some treatment procedures with acids, bases, reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate can be used.

In each of the reaction processes for the preparation of said compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ix), (I) and (I), or of their salts and in any reaction for the synthesis of the crude material of these compounds, solvents which are commonly known may be used during the reaction.

For example, the following generally 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, petroether; carboxylic acids, such as formic acid, acetic acid; and water.

In addition, the solvents used in these reactions can be used as single solvents or as mixtures of two to 6 solvents.

In addition, this reaction can be performed in the presence of amines, such as triethylamine, N, N-diisopropylamine, pyridine, N-methylmorpholine, or a base, such as sodium hydroxide, potassium carbonate. Alternatively, this reaction can be performed in the presence of an acid, such as hydrochloric acid, sulfuric acid, acetic acid.

Compounds obtained by the above-mentioned methods: (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (I) and (I), can be isolated and purified. by conventional separation methods, such as recrystallization, distillation, chromatography. If the compounds of the present invention are: (le), (lf), (lh), (li) and (lj), or comparative compounds (la), (lb), (lc), (ld)

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54504 Β1 and (lg), are obtained in free form, they can be converted into their salts by known methods or with some similar processes (eg neutralization), or vice versa, if obtained in salt form, they can be converted into free form or other salts, using known methods or some similar methods. If these compounds are obtained as racemates, they can be separated into the d-form and the I-form, by conventional means of optical separation.

The raw material compounds of compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ix), (II) and (I1), or their salts, are not particularly limited until they interfere with this reaction. Examples of these salts are the same as the salts of compounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ix), (I) and (I).

In any of the above-mentioned manufacturing processes or processes, if desired, the compounds (lo) can be synthesized by further application of one or a combination of known reactions, such as protection / deprotection reactions, acylation reactions, alkylation reactions, hydrogenation reactions, oxidation reactions, reduction reactions, chain extension reactions, substitution replacement reactions.

If the target products are obtained by the above-mentioned reactions in free form, they can be converted into the corresponding salts by conventional methods, or if obtained in the form of salts, they can be converted into the free form or other salts by conventional methods. The resulting 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.

If the compound (lo) is present as a configurational isomer, diastereomer, or conformer, if desired, it can then be isolated by the above-mentioned isolation and purification methods. If the compound (lo) is present as a racemate, it can be separated into the d-form and / -form by conventional means of optical separation.

The compound (lo) can be used in the form of a prodrug. A prodrug of a compound (lo) is a compound that is converted to a compound by (lo) reactions using enzymes or gastric acid, under physiological conditions in vivo. In fact, the prodrug encompasses

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54504 Β1 compounds that are converted to compounds by (lo) enzymatic oxidation, reduction and hydrolysis, or compounds that are converted to compounds by (lo) hydrolysis by gastric acid.

Prodrugs of compound (lo) are compounds in which an amino group in compound (lo) is acylated, alkylated or phosphorylated (e.g., an amino group in compound (lo) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1 1,3-oxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); the hydroxyl group in compound (lo) is acylated, alkylated, phosphorylated or borotylated (e.g. the hydroxyl group in compound (lo) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated); the carboxyl group in compound (lo) is esterified or amidated (e.g. the carboxyl group in compound (lo) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, 5-methyl-ester-4-methyl-idyl-ester ) methyl-esterified, cyclohexyloxycarbonylethyl-esterified or methylamidated). These compounds can be prepared by known methods from compound (Io). Prodrugs of compound (lo) can be converted to compound (lo) under physiological conditions, as described in Development of Drugs Vol. 7 Molecular Design published in 1990, in Hirokawa Shoten, pages 163 to 198.

The compound of the present invention has excellent inhibitory activity for PDE10A and is useful for the following diseases and symptoms in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats, especially humans): mental disorders (e.g. brief psychotic disorder, divided psychotic disorder); psychosis, caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opiates, or phencyclidine; delusion disorder; anxiety disorder; movement disorder; mood disorder; major depressive disorder; major depressive disorder combined with a psychotic disorder containing some delusional disorder or schizophrenia; episodes of major depression of mild, moderate, or severe type; manic episode or mixed mood episode; an episode of hypomanic mood; a depressive episode with atypical features; depressive episode with melancholic characteristics; depressive episode with catatonic

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54504 Β1 characteristics; mood episodes conceived after childbirth; depression after stroke; dysthymic disorder; minor depressive disorder; autism; drug-dependent neurodegenerative disorder; neurodegeneration associated with cerebral trauma; stroke-related neurodegeneration; neurodegeneration associated with cerebral infarction; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizures; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy; Alzheimer's disease; dementia; multi-infarct dementia; alcoholic dementia or dementia from other drugs; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; dementia due to AIDS; fronto-temporal dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorder (e.g., reading disorder, math disorder, or written expression disorder); attention deficit / hyperactivity disorder; cognitive impairment due to age; premenstrual dysphoric disorder; depressive postpsychotic disorder schizophrenia; bipolar disorder, comprising bipolar I disorder, bipolar II disorder; cyclothymic disorder; Parkinson's disease; Huntington's disease; paranoid; schizophrenia (e.g. paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia); schizophrenic disorder; schizoaffective disorder of the delusion or depressive type; paranoid personality disorder; schizophrenic personality disorder; obesity; metabolic syndrome; non-insulin dependent diabetes (NIDDM); glucose intolerance;

The compound of the present invention is particularly useful for the prevention or treatment of schizophrenia.

Since the compound of the present invention shows excellent metabolic stability, superior therapeutic effects are expected for the above-mentioned diseases, even at low dosages.

The compound of the present invention may be administered safely, as is, or in a dosage form, manufactured by any of the known methods for the manufacture of pharmaceutical formulations (e.g., by the methods described in Japanese Pharmacopoeia), such as tablets. sugar-coated tablet

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54504 Β1 film, sublingual tablet, oral disintegration tablet and buccal), pills, powders, granules, capsules (including soft capsule and microcapsule), lozenges, syrups, liquid dosage forms, emulsions, controlled release formulations (eg rapid-release preparation) release, sustained release preparation, sustained release microcapsules), aerosols, films (eg oral disintegrating film, adhesive film for application to the oral mucosa), injections (eg subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation infusions, skin absorbents, ointments, lotions, patches, suppositories (eg rectal suppository, vaginal suppository), pellets, transnasal preparations, pulmonary preparations, inhalants eyes, oral or parenteral preparations (e.g. intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradernal, ophthalmic instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, directly in injury).

Here, conventional organic and inorganic carrier substances are used in the formulation of the raw materials, as a pharmaceutically acceptable carrier. Carriers are added as fillers, lubricants, binders and disintegrants in solid formulations; and as solubilizing agents, suspending agents, isotonizing agents, buffers and as mitigating agents in liquid formulations. If desired, additives of formulations can be used, such as antiseptics, antioxidants, colorants, sweeteners.

Suitable examples of fillers are as follows: lactose, invert sugar, D-mannitol, Dsorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pululane, silica aluminide silicate and magnesium metasilicyl aluminate.

Suitable examples of lubricants are magnesium stearate, calcium stearate, talc and colloidal silicon dioxide.

Suitable examples of binders are as follows: α-starch, invert sugar, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, invert sugar, D-mannitol, trehalose, dextrin pullulase, hydroxypropylpropylpropylpropylpropylpropylpropylpropylpropylpropylpropyl

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54504 Β1

Suitable examples of disintegrants are as follows: lactose, invert sugar, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride and low-substituted hydroxylopropyl.

Suitable examples of the solvent are as follows: water for injections, saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Suitable examples of solubilizing agents are as follows: polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

Suitable examples of suspending agents are as follows: surfactants, such as stearyl triethanolamine, sodium lauryl sulfate, laurylamino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearate; hydrophilic polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose; polysorbates and polyoxyethylene-hardened castor oil.

Suitable examples of isotonizing agents are sodium chloride, glycerin, D-mannitol, Dsorbitol and glucose.

Suitable examples of buffers are buffer solutions of phosphate, acetate, carbonate and citrate.

Suitable examples of mitigating agents include benzyl alcohol.

Suitable examples of antiseptics are para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Suitable examples of antioxidants are sulfites and ascorbates.

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54504 Β1

Suitable examples of colorants are edible terra colors, soluble in water (e.g. edible dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and 2); water-insoluble dyes with metals (e.g. aluminum salts of the above-mentioned edible tera oils, water-soluble), natural dyes (e.g. β-carotene, chlorophyll, red iron oxide).

Suitable examples of sweeteners are sodium saccharin, dipotassium glycyrrhizinate, aspartame and stevia.

The medical compositions of the present invention can be prepared by conventional methods in the field of formulation technology, for example, by the methods described in Japanese Pharmacopoeia. Specific manufacturing processes for formulations are described in more detail below.

The content of the compounds of the present invention in the medical compositions of the present invention varies depending on the dosage form and the dose of the compounds of the present invention. For example, this content ranges from about 0.01 to 100% by weight, preferably from 0.1 to 95% by weight, based on the total weight of the composition.

The dosage of the compounds of this invention depends on the objectives of the injection, the route of administration, the target diseases, the symptoms. For example, in the case of oral administration to patients with schizophrenia (adults, body weight approximately 60 kg), usually as a single dose, it ranges from approximately 0.1 to 20 mg / kg body weight, preferably from approximately 0.2 to 10 mg / kg body weight, more preferably from about 0.5 to 10 mg / kg body weight, and this dose is preferably administered once a day, or divided, several times a day (e.g. χ times).

These compounds may be administered as the sole active agent or in combination with other pharmaceutical agents, such as other agents used in the treatment of psychosis, in particular schizophrenia and bip bipolar disorder, obsessive / compulsive disorder, major depression, Parkinson's disease, Alzheimer's diseases, cognitive inconsistencies and / or memory loss, such as nicotinic α7 agonists, nicotinic α7 partial agonists, nicotinic α7 positive allosteric modulators, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, calcium channel blockers

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54504 Β1 channels, muscarinic m1 and m2 modulators, adenosine receptor modulators, amines, glycine transporter 1 inhibitors, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, selective serotonin reuptake inhibitors, norophyrene and serotonin resorption inhibitors , triple resorption inhibitors, cannabinoid modulators and cholinesterase inhibitors (eg donepezil, rivastigmine and galantamine). In these combinations, each active ingredient may be administered either in accordance with its usual dosage range or with a dose below its usual dosage range, and may be administered either in parallel or sequentially.

Drugs suitable in combination with the compounds of this invention are, but are not limited to, other drugs suitable for schizophrenia, such as Haldol, Clozaril, Zyprexa, Risperdal, Abilify, Geodon, Invega, and 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, Regtah, Mirapex, Tasmar, Kemadrin, Artane, and Cogentin; agents used in the treatment of 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, Sodpeh, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen, and Clioquinol; agents used in the treatment of dementia, including, but not limited to, Mellaril, Haldol, Risperdal, Sodpeh, Aricept, and Exelon; agents used in the treatment of epilepsy, including, but not limited to, Dilantin, Luminal, Tegretol, Depakote, Depakene, Zarontin.Neurontin, Barbita, Solfeton, and Felbatol; agents used in the treatment of multiple sclerosis, including, but not limited to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azathioprine, TgehaN, and Sorahope; agents used in the treatment of Huntington's disease, including, but not limited to, Elavil, Tofranil, Norpramin, Pamelor, Paxil, Prozac, Zoloft, Nitoman, Haldol, Thorazin, Mellaril, Dogmatil, Seroquel, Clozaril, and Risperdal; agents useful in the treatment of diabetes, including, but not limited to, PPAR ligands (e.g., agonists, antagonists, such as Rosiglitazone, Troglitazone, and Pioglitazone), insulin secretagogues, e.g. sulfonylurea drugs, such as Glyburide, Glimepiride, Chlopropamide, Tolbutamide and Glipizide and non-sulfonyl secretagogues), α-glucosidase inhibitors (such as Acarbose, Miglitol and Voglibose), insulin sensors such as γ-agonists, e.g. PPAR-agonists.

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54504 Β1 glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors and 11-beta-HSD inhibitors), hepatic glucose lowering compounds (such as glucagon and metformin antagonists, eg Glucophage and Glucophage XR), insulin and insulin derivatives (both forms for long and short action and insulin formulations); and anti-obesity drugs, including, but not limited to, β-Z agonists, CB-1 agonists, neuropeptide Y5 inhibitors, Ciliary Neurotrophic Factor, and derivatives (e.g. Axokin), appetite suppressants (e.g. Sibutramine) and lipase inhibitors (e.g. Orlistat).

The form of administration of the concomitant drugs with the compound of the present invention is particularly limited and acceptable as long as the compound of the present invention is combined with the concomitant drugs at the time of administration. Examples of these forms of administration are as follows:

(1) Administration of a single formula, obtained by simultaneous formulation of a compound of the present invention with an accompanying drug, (2) Simultaneous administration, by the same administration of two types of formulations, obtained by independent formulation of a compound of the present invention and an accompanying drug, (3) by the same route of administration, two types of formulations, obtained by independent formulation of the compounds of the present invention and the concomitant drug, (4) Simultaneous administration, and by different routes of administration, two types of formulations, obtained by independent formulation of the compounds of this invention and the accompanying drug, (5) Administration at different times, different routes of administration, two types of formulations, obtained by independent formulation of the compounds of this invention and the accompanying drug. (For example, administering in order the composition of the present invention and the accompanying drug, or administering in reverse order). These forms of administration are summarized below and abbreviated as the accompanying agent of the present invention.

When a concomitant agent of the invention is administered, a concomitant drug and a compound of the present invention may be administered simultaneously, or a compound of the present invention may be administered after administration of the concomitant drug, or a concomitant drug may be administered after administration of a compound of the invention. When administered at different times, the time difference depends on the active ingredients to be administered, the form of the drug and the administration procedure. For example, when the concomitant drug is first administered, the compound of the present invention may be administered from 1 min to * day, preferably within 10 min to 1 day, and more preferably within 15 min to 1 h, after administration of the concomitant drug. However, if the compound of the present invention is administered first, the concomitant drug is sh

54504 Β1 can be administered within 1 min to 1 day, preferably within 10 min to 6 h, and more preferably within 15 min to 1 h after administration of the compounds of this invention.

If there are no problems with the side effects of the accompanying drugs, any dose can be determined. The daily dose of the accompanying check depends on the dose, the subject to whom it is administered, the route of administration, the target disease, the symptoms. For example, in the case of oral administration to patients with schizophrenia (adults, body weight of approximately 60 kg), the normal daily dose ranges 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. Preferably, this dose is administered from once a day to several times a day (e.g. χ times).

If a compound of the present invention is used in combination with a concomitant drug, the respective doses may be reduced within the safe range, with consideration of the adverse effects of the respective drugs.

The accompanying agent of the present invention shows low toxicity. For example, a compound of the present invention and / or the above-mentioned concomitant drug may be combined with a pharmaceutically acceptable carrier, in accordance with a known method of preparing a medical composition, such as tablets (including sugar-coated tablets and film-coated tablets), agents in powders, granular agents, capsules (including soft capsules), liquids, solutions for injection, suppositories, sustained release agents. These compositions may be safely administered orally or non-orally (e.g., including local, rectal, and venous routes).

Pharmaceutically acceptable carriers, which may be used in the manufacture of the concomitant agent of the present invention, may be the same as those used in the medical composition of the present invention, as mentioned above.

The mixing ratio between the compounds of the present invention and the concomitant drug in the concomitant drug of the present invention may be appropriately selected depending on the subject to be administered, the route of administration and the disease.

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The previously mentioned concomitant drugs can be combined in the appropriate proportion, if two or more drugs are combined.

The dose of concomitant medication can be chosen appropriately, depending on the dose used clinically. In addition, the mixing ratio between the compounds of the present invention and a concomitant drug may be appropriately selected, based on the subjects to be administered, the routes of administration, the target diseases, the symptoms, the combinations. For example, if the subjects to be administered are human beings, an accompanying drug may be used in a content ranging from 0.01 to 100 parts by weight, relative to 1 part by weight of the compounds of the present invention.

For example, the content of a compound of the invention in the concomitant agent of the present invention depends on the form of the drug in the formulation. It is usually present in the range of 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% by weight, relative to the total formulation.

The content of a concomitant drug in the concomitant agent of the present invention varies with the form of the drug in the formulation. It is usually present in the range of 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% by weight, relative to the total formulation.

The content of an additive, such as carriers, in the accompanying agent of the present invention varies with the form of the drug in the formulation. It is usually present in the range of about 1 to 99.99% by weight, preferably from about 10 to 90% by weight, relative to the total formulation.

When a compound of the invention and an accompanying drug are formulated independently, the same contents may be used.

Since doses may fluctuate under different conditions, as mentioned above, doses less than the above-mentioned doses may be sufficient, and it may be necessary to administer doses in excess of this range.

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Examples

The present invention will be explained in detail below, through reference examples, embodiments, formulation examples, and experimental examples. Since these are merely examples, the present invention will not be limited to these examples, but the present invention may be modified within a scope which will not depart from the scope of the present invention.

In the reference examples and embodiments that follow, room temperature typically refers to approximately 10 ° C to 35 ° C. In the case of%, in terms of yield, this% denotes mol%, and in the case of the solvent used in chromatography, this% denotes vol%, while% in all other cases denotes mass%. In the proton spectrum, NMR, OH, and NH protons, which cannot be identified due to bandwidth, are not even recorded in the data. Kiesselgel 60 from Megsk &amp; Co., Inc. was used in the silica gel chromatography, and Chromatorex NH silica gel from Fuji Silysia Chemical Ltd. was used in the base chromatography.

Abbreviations used in other parts of the text refer to 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

CDCIs: deuterochloroform

DMSO-de: deutero-dimethylsulfoxide ¹1 H-NMR: proton nuclear magnetic resonance

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HPLC: high performance liquid chromatography

THF: tetrahydrofuran

DMF: N, N-dimethylformamide

DMSO: dimethylsulfoxide

NMP: N-methylpyrrolidone

COPD: 1-hydroxybenzotriazole

WSC: Hydrogen chloride 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide

HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

DMTMM: 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl [morpholinium chloride n-hydrate DBU: 1,8-diazabicyclo [5.4.0] -7-undecene

LC-MS: liquid chromatography / mass spectroscopy

ESI: electrospray ionization

CDI: N, N-carbonyldiimidazole dba: dibenzylideneacetone

DIBAL: diisobutylaluminum hydride

DME: 1,2-dimethoxyethane

DPPA: diphenylphosphoryl azide

HMPA: hexamethylphosphorus triamide selectfluoro: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluorooborate)

TEA: triethylamine

TFA: trifluoroacetic acid

TMSCI: trimethylsilyl chloride

Xantphos. 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

Cape: retention time

All reagents and solvents were of commercial quality and were used without further purification. Chromatography on the column was performed using silica gel of Megsk silica gel 60 (230-400 mesh). Compounds and / or intermediates were purified by preparative high performance liquid chromatography (HPLC) using a Gilson High through Put purification system.

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The columns were with the reverse phase of the company YMC CombiPrep Rgo C18, S-5 mm, 19 * 50 mm. A gradient elution (flow rate 20 mL / min) was used, typically starting with a mixture of 5% acetonitrile / 95% water and then advancing to 100% acetonitrile over a period of 7 min. All solvents contained 0.1% trifluoroacetic acid (TFA).

Mass spectrometric analysis was performed according to liquid chromatography / mass spectroscopy (LCMS) procedures. This procedure uses the VVaters LC-MS System (Agilent HP 1100 HPLC and Micromass ZMD mass spectrometer in the LCMS instrument, in the column chromatography the product of CAPCELL PAK C18, UG120, S-3 mm, 1.5 χ 35 mm was used and a solvent system with a gradient of 5-95% acetonitrile in water, with 0.04% TFA, over a period of 3.60 min (flow 0.5 mL / min, molar mass range 200-800; with cone voltage 20 V; column temperature 40 ° C) . All masses refer to the masses of protonated parent ions.

Reference example 1

3 - {[3- (Trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione ^v tT ^Μθ hn^{, n}

Dissolve 3- (trifluoromethyl) aniline (34.6 g, 215 mmol) in a mixture of concentrated hydrochloric acid (64 mL) and water (64 mL). To the resulting mixture was added dropwise a solution of sodium nitrite (16.6 g, 240 mmol) in water (100 mL), at 0 ° C. This mixture was stirred at 0 ° C for 1 h. To the resulting diazonium salt solution was added dropwise 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), at room temperature). This mixture was stirred for 18 h at room temperature, using a mechanical stirrer. The orange precipitate was filtered off, then the orega with water (150 mL χ 3), 50% ethanol in water (100 mL χ 2) and n-hexane (100 ml_) and then dried under vacuum at 50 ° C for 5 h to give 52.7 g (90%) 3 - {[3 (trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione, as an orange substance.

116

54504 Β1 ¹1 NMR (400 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.63 (s, ZN), 7.45-7.44 (m, 1H),

7.58-7.51 (m, 2 H), 7.66 (s, 1 H), 14.68 (s, 1 H). LC-MS (MH &amp; lt; + &amp; gt;) 273.10.

Reference example2

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

A mixture of 3 - {[3- (trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione (4.3 g, 15.8 mmol) and N, N-dimethylformamide dimethyl acetal (40 mL) was heated in an oil bath at 120 ° C for 5 h. . 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 a black oil, which is used in the next step without further purification.

LC-MS (MH⁺) 338.16.

Reference example 3

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

<img file="RS54504B1_D0023.tif" />

To a solution of 4- (trifluoromethyl) aniline (1090 mg, 6.80 mmol) in 5 mL of water and 5 mL of concentrated hydrogen chloride solution, sodium nitrite (563 mg, 8.16 mmol) in 4 mL of water was added dropwise at 0 ° C. , and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (1670 mg, 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 this reaction mixture. This mixture was stirred overnight at room temperature, filtered, oregeo with water, ΕίΟΗ / ΗδΟ (1: 1) and hexane, and dried to give 3 - {[4- (trifluoromethyl) phenyl] hydrazone} pentane-2,4-dione. (580 mg, 31%).

117

54504 Β1 ¹Η NMR (300 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.62 (s, ZN), 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

<img file="RS54504B1_D0024.tif" />

Dissolve 3 - {[4- (trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione (580 mg, 2.13 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA) and reflux this mixture. 4 h, then concentrated under reduced pressure to give crude 3- [3 (dimethylamino) prop-2-enoyl] -1- [4- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 5

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

<img file="RS54504B1_D0025.tif" />

To a solution of 3-chloroaniline (1000 mg, 7.87 mmol) in 5 mL of water and 5 mL of concentrated hydrogen chloride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of water was added dropwise at 0 ° C, then this mixture at 0 ° C for 1 h. A solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (866 mg, 8.66 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / NJO (1: 1) and hexane, and dried to give 3 - [(3-chlorophenyl) hydrazono] pentane-2,4-dione (450 mg). , 24%).

LCMS: m / z = 239 [³⁵CI, M⁺+ H],

Reference example 6

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54504 Β1

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

<img file="RS54504B1_D0026.tif" />

Dissolve 3 - [(3-chlorophenyl) hydrazono] pentane-2,4-dione (450 mg, 1.89 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. it is then concentrated under reduced pressure to give crude 1- (3-chlorophenyl) -3- [3 (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which is used in the next step without further purification.

Reference example 7

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

<img file="RS54504B1_D0027.tif" />

To a solution of 2-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(2-methoxyphenyl) hydrazono] pentane-2,4-dione (1500 mg, 79%).

LCMS: m / z = 235 [M⁺+ H],

Reference example 8

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

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Dissolve 3 - [(2-methoxyphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.14 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, it is then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (2-methoxyphenyl) pyridazin-4 (1H) -one, which is used in the next step without further purification.

<img file="RS54504B1_D0028.tif" />

Reference example 9

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

<img file="RS54504B1_D0029.tif" />

To a solution of 4-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / NgO (1: 1) and hexane and dried to give 3 - [(4-methoxyphenyl) hydrazono] pentane-2,4-dione (950 mg, 50%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (s, ZN), 2.62 (s, ZN), 3.86 (s, ZN), 6.96-6.98 (m, 2H), 7.38-7.41 (m, 2H), 14.99 (s, 1 H).

Reference example 10

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

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54504 Β1

<img file="RS54504B1_D0030.tif" />

Dissolve 3 - [(4-methoxyphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.14 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA) and reflux this mixture for 4 h. it was then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (4-methoxyphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 11

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

<img file="RS54504B1_D0031.tif" />

<img file="RS54504B1_D0032.tif" />

<img file="RS54504B1_D0033.tif" />

To a solution of 3-fluoroaniline (1000 mg, 9.00 mmol) in 5 mL of water and 5 mL of concentrated hydrogen chloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water, 0 ° C was added dropwise, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / FhO (1: 1) and hexane and dried to give 3 - [(3-fluorophenyl) hydrazono] pentane-2,4-dione (650 mg, 33%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (s, ZN), 2.62 (s, ZN), 6.90 (dt, J = 2.4, 8.0 Ηζ, 1H), 7.11 (dd, J = 1.6, 8.0 Ηζ, 1H), 7.21 (td, J = 2.4, 10.0 Ηζ, 1H), 7.34-7.39 (m, 1H), 14.61 (s, 1H).

Reference example 12

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

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54504 Β1

<img file="RS54504B1_D0034.tif" />

Dissolve 3 - [(3-fluorophenyl) hydrazono] pentane-2,4-dione (650 mg, 2.93 mmol) in 10 mL

N, N-dimethylformamide dimethylacetal (DMF-DMA), and this mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (3-fluorophenyl) pyridazine. -4 (1H) -one, which was used in the next step without further purification.

Reference example 13

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

Η Me

To a solution of 2-fluoroaniline (1000 mg, 9.00 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water was added dropwise at 0 ° C. so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / hbO (1: 1) and hexane and dried to give 3 - [(2-fluorophenyl) hydrazono] pentane-2,4-dione (1280 mg, 64%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.62 (s, ZN), 7.14-7.24 (m, ZN), 7.77 (d, J = 8.0 Hz, 1H), 14.71 (s, 1H).

Reference example 14

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

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Dissolve 3 - [(2-fluorophenyl) hydrazono] pentane-2,4-dione (600 mg, 2.70 mmol) in 10 mL

N, N-dimethylformamide dimethylacetal (DMF-DMA), and this mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (2-fluorophenyl) pyridazine. -4 (1H) - one, which is used in the next step without further purification.

Reference example 15

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

<img file="RS54504B1_D0035.tif" />

<img file="RS54504B1_D0036.tif" />

<img file="RS54504B1_D0037.tif" />

To a solution of 4-fluoroaniline (1000 mg, 9.00 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water was added dropwise at 0 ° C, then this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, E1ON / NgO (1: 1) and hexane and dried to give 3 - [(4-fluorophenyl) hydrazono] pentane-2,4-dione (1200 mg, 60%).

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.49 (s, ZN), 2.61 (s, ZN), 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

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<img file="RS54504B1_D0038.tif" />

Dissolve 3 - [(4-fluorophenyl) hydrazono] pentane-2,4-dione (650 mg, 2.93 mmol) in 10 mL

N, N-dimethylformamide dimethylacetal (DMF-DMA), and this mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (4-fluorophenyl) pyridazine. -4 (1H) -one, which was used in the next step without further purification.

Reference example 17

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

<img file="RS54504B1_D0039.tif" />

<img file="RS54504B1_D0040.tif" />

<img file="RS54504B1_D0041.tif" />

To a solution of 4-chloroaniline (1000 mg, 7.87 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (1023 mg, 10.23 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / NJO (1: 1) and hexane and dried to give 3 - [(4-chlorophenyl) hydrazono] pentane-2,4-dione (1680 mg, 90%). ¹1 H NMR (400 MHz, CDCl 3)₃): b ppm 2.49 (s, ZN), 2.61 (s, ZN), 7.33-7.39 (m, 4H), 14.70 (s, 1H).

Reference example 18

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

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<img file="RS54504B1_D0042.tif" />

Dissolve 3 - [(4-chlorophenyl) hydrazono] pentane-2,4-dione (600 mg, 2.52 mmol) in 10 mL

N, N-dimethylformamide dirnethylacetal (DMF-DMA), and this mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 1- (4-chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 19

3 - [(2-Methylphenyl) hydroxide] penta n-2,4-d ion

<img file="RS54504B1_D0043.tif" />

<img file="RS54504B1_D0044.tif" />

To a solution of 2-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0 ° C and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, E (ON / NgO (1: 1) and hexane and dried to give 3 - [(2-methylphenyl) hydrazono] pentane-2,4-dione mg, 49%) LCMS: m / z = 219 [M⁺+ H].

Reference Example 20 3- [3- (Dimethylamino) prop-2-enoyl] -1- (2-methylphenyl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0045.tif" />

125

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Dissolve 3 - [(2-methylphenyl) hydrazono] pentane-2,4-dione (1000 mg, 4.59 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. it is then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (2-methylphenyl) pyridazin-4 (1H) -one, which is used in the next step without further purification.

Reference example 21

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

<img file="RS54504B1_D0046.tif" />

»B '

To a solution of 3-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / NgO (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

Dissolve 3 - [(3-methylphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.29 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2

126

54504 Β1 enoyl] -1- (3-methylphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 23

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

Me jf Me hnⁿ

To a solution of 3-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / H2O (1: 1) and hexane and dried to give 3 - [(3-methoxyphenyl) hydrazono] pentane-2,4-dione (840 mg, 44%).

LCMS: m / z = 235 [M⁺+ HJ.

Reference example 24

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

Dissolve 3 - [(3-methoxyphenyl) hydrazono] pentane-2,4-dione (500 mg, 2.14 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, it was then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (3-methoxyphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

127

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Reference example 25

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

<img file="RS54504B1_D0047.tif" />

To a solution of 2- (trifluoromethyl) aniline (1.09 g, 6.80 mmol) in 5 mL of water and 5 mL of concentrated hydrogen chloride solution was added dropwise sodium nitrite (563 mg, 8.16 mmol) in 4 mL of water, at 0 °. C, and this mixture was stirred at 0 ° C for 1 h. 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. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / hhO (1: 1) and hexane and dried to give 3 - {[2- (trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione ( 634 mg, 33%).

1 H NMR (300 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.63 (s, ZN), 7.24-7.29 (m, 1H), 7.60-7.66 (m, 2H), 7.96 (8.4 Hz, 1H) ), 15.06 (s, 1 H).

Reference example 26

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

<img file="RS54504B1_D0048.tif" />

Dissolve 3 - {[2- (trifluoromethyl) phenyl] hydrazono} pentane-2,4-dione (634 mg, 2.33 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture. 4 h, then concentrated under reduced pressure to give crude 3- [3 (dimethylamino) prop-2-enoyl] -1- [2- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one, which is used in the following step without further purification.

Reference example 27

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

128

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<img file="RS54504B1_D0049.tif" />

To a solution of 4-morpholin-4-ylaniline (1000 mg, 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (465 mg, 6.74 mmol) in 4 mL of water was added dropwise to 0 ° C, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / NgO (1: 1) and hexane and dried to give 3 - [(4-morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione (900 mg, 55%).

LCMS: m / z = 290 [M⁺+ H].

Reference Example 28 3- [3- (Dimethylamino) prop-2-enoyl] -1- (4-morpholin-4-ylphenyl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0050.tif" />

<img file="RS54504B1_D0051.tif" />

Dissolve 3 - [(4-morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione (900 mg, 3.11 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and mix this reflux for 4 h, then concentrate under reduced pressure to give crude 3- [3- (dimethylamino) prop-

2-enoyl] -1- (4-morpholin-4-ylphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 29

3- (Phenylhydrazono) pentane-2,4-dione

129

54504 Β1

<img file="RS54504B1_D0052.tif" />

To a solution of aniline (2000 mg, 21.50 mmol) in 30 mL of acetic acid and 5 mL of concentrated hydrogen chloride solution, sodium nitrite (1780 mg, 25.80 mmol) in 8 mL of water was added dropwise at 0 ° C and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (5290 mg, 64.50 mmol) and acetylacetone (2795 mg, 27.95 mmol) in 20 mL of ethanol and 12 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / NgO (1: 1) and hexane and dried to give 3- (phenylhydrazono) pentane-2,4-dione (2955 mg, 67%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (s, ZN), 2.61 (s, ZN), 7.21 (dd, J = 8.0, 4.4 Hz, 1H), 7.41 (d, J = 4.4 Hz, 4H) , 14.74 (s, 1 H).

Reference example 30

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

<img file="RS54504B1_D0053.tif" />

Dissolve 3- (phenylhydrazono) pentane-2,4-dione (470 mg, 2.30 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, then concentrate under reduced pressure to give crude 3- [3- (dimethylamino) prop-2-enoyl] -1-phenylpyridazin-4 (1H) -one, which was used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, DMSO-d 6): δ ppm 2.84 (s, ZN), 3.11 (s, ZN), 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).

Reference example 31

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

130

54504 Β1

<img file="RS54504B1_D0054.tif" />

To a solution of 4-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / hhO (1: 1) and hexane and dried to give 3 - [(4-methylphenyl) hydrazono] pentane-2,4-dione (480 mg, 24%).

¹1 H NMR (400 MHz, CDCl 3)₃): b ppm 2.36 (s, ZN), 2.49 (s, ZN), 2.60 (s, ZN), 7.21 (d, J = 8.0 Ηζ, 2H), 7.32 (d, J = 8.0 Ηζ, 2H), 14.82 (s, 1 H).

Reference example 32

3- [3- (Dimethylamino) prop2-enoyl] -1- (4-methylphenyl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0055.tif" />

Dissolve 3 - [(4-methylphenyl) hydrazono] pentane-2,4-dione (462 mg, 2.12 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, it is then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1- (4-methylphenyl) pyridazin-4 (1H) -one, which is used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, DMSO-d 6): δ ppm 2.38 (s, ZN), 2.84 (s, ZN), 3.10 (s, ZN), 6.53 (d, J = 8.0 Hz, 1H), 7.37 d, J = 8.0 Ηζ, 2H), 7.58 (d, J = 8.0 Hz, 2H), 8.76 (d, J = 8.0 Ηζ, 1H).

131

54504 Β1

Reference example 33

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

<img file="RS54504B1_D0056.tif" />

To a solution of 2- (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 15 mL of acetic acid and

2.5 mL of concentrated hydrogen chloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / HaO (1: 1) and hexane and dried to give 3 - {[2- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione ( 1590 mg, 94%).

LCMS: m / z = 271 [M⁺ + H].

Reference example 34

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

<img file="RS54504B1_D0057.tif" />

Dissolve 3 - {[2- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione (500 mg, 1.85 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA) and reflux this mixture. 4 h, then concentrated under reduced pressure to give crude 1- [2 (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which is used in the following step without further purification.

Reference example 35

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

132

54504 Β1

<img file="RS54504B1_D0058.tif" />

To a solution of 3 ~ (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution was added dropwise sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water, at 0 mL. ° C, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, orego with water, EtOH / NgO (1: 1) and hexane and dried to give 3 - {[3- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione ( 1500 mg, 89%).

LCMS: m / z = 271 [M⁺+ H].

Reference example 36

1- [3- (Difluoromethoxy) phenyl] -3 ~ [3- (dimethylamino) prop ”2-enoyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0059.tif" />

Dissolve 3 - {[3- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione (800 mg, 2.96 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA) and reflux this mixture. h, then concentrated under reduced pressure to give crude 1- [3- (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 37

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

133

54504 Β1

<img file="RS54504B1_D0060.tif" />

To a solution of 4- (difluoromethoxy) aniline (1000 mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise, then 0 ° C, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / FhO (1: 1) and hexane and dried to give 3 - {[4- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione ( 1400 mg, yield 82%).

LCMS: m / z = 271 [M⁺+ H].

Reference example 38

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

<img file="RS54504B1_D0061.tif" />

<img file="RS54504B1_D0062.tif" />

Dissolve 3 - {[4- (difluoromethoxy) phenyl] hydrazono} pentane-2,4-dione (600 mg, 2.22 mmol) in 10 mL of N, N-dimethylformamide dimethyl acetal (DMF-DMA), and reflux this mixture. 4 h, then concentrated under reduced pressure to give crude 1- [4 (difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2 “enoyl] pyridazin-4 (1H) -one, which is used in the following step without further purification.

Reference example 39

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

134

54504 Β1

<img file="RS54504B1_D0063.tif" />

To a solution of 2-morpholin-4-ylaniline (1000 mg, 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (465 mg, 6.74 mmol) in 4 mL of water was added dropwise to 0 ° C, and this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / FhO (1: 1) and hexane and dried to give 3 - [(2-morpholin-4-ylphenyl) hydrazorio] pentane-2,4-dione (1000 mg, 62%).

LCMS: m / z - 290 [M⁺ + H].

Reference example 40

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

<img file="RS54504B1_D0064.tif" />

Dissolve 3 - [(2-morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione (1000 mg, 2.46 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and mix this reflux for 4 h, then concentrate under reduced pressure to give crude 3- [3 (dimethylamino) prop-2-enoyl] -1- (2-morpholin-4-ylphenyl) pyridazin-4 (1H) -one, which is used in the next step without further purification.

Reference example41

3- (Pyridin-3-ylhydrazono) pentane-2,4-dione

<img file="RS54504B1_D0065.tif" />

135

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To 3-aminopyridine (564 mg, 6.00 mmol) was added 4 mL of concentrated sulfuric acid and 1.2 mL of water at 0 ° C, and this mixture was stirred at room temperature until clear. To this reaction mixture was added a solution of sodium nitrite (414 mg, 6.00 mmol) in water (1.2 mL), at 0 ° C. This mixture was stirred for several minutes (&gt; 15 min). A solution of diazonium salt was added to 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. This mixture was stirred at 0 ° C for 30 min and at room temperature for 30 min. This reaction mixture was added to 120 mL of a saturated solution of №gSO 2 in water. This mixture was extracted with dichloromethane, washed with water and brine, dried over IagbOd and concentrated under reduced pressure to give 3- (pyridin-3-ylhydrazono) pentane-2,4-dione (242 mg, 20% yield).

LCMS: m / z = 206 [M⁺ + H].

Reference Example 42 3- [3- (Dimethylamino) prop-2-enoyl] -1-pyridin-3-ylpyridazin-4 (1H) -one

Dissolve 3- (pyridin-3-ylhydrazono) pentane-2,4-dione (200 mg, 0.98 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, then concentrated under reduced pressure to give crude 3- [3- (dimethylamino) prop-2-enoyl] -1-pyridin-3-ylpyridazin-4 (1H) -one, which was used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, CDCl 3): b ppm 2.90 (s, ZN), 3.15 (s, ZN), 5.64 (d, J = 11.6 Hz, 1H), 6.74 (d, J = 8.4 Ηζ, 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 Ηζ, 1H) ).

Reference Example 43 3- (Pyridin-4-ylhydrazono) pentane-2,4-dione

136

54504 Β1

<img file="RS54504B1_D0066.tif" />

4-Aminopyridine (470 mg, 5.00 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and solid sodium nitrite (350 mg, 5.00 mmol) was added over 10 min. Crushed pieces of ice (50 g) are added to this solution. This mixture was added at 0 ° C to an appropriate suspension of 2,4-pentanedione (500 mg, 5.00 mmol) and potassium acetate (20 g) in ethanol (250 mL). This solution was stirred for 15 min, 250 mL of a saturated solution of IagSO 2 in water was added, extracted with dichloromethane, washed with water and brine, dried over Na 2 SO 4, and concentrated under reduced pressure to give 3 (pyridin-4-ylhydrazono) pentane-2,4 -dione (149 mg, yield 14%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.62 (s, ZN), 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-ylpyridazin-4 (1H) -one

<img file="RS54504B1_D0067.tif" />

<img file="RS54504B1_D0068.tif" />

Dissolve 3- (pyridin-4-ylhydrazono) pentane-2,4-dione (120 mg, 0.58 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, then concentrate under under reduced pressure to give crude 3- [3- (dimethylamino) prop-2enoyl] -1-pyridin-4-ylpyridazin-4 (1H) -one, which was used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, CDCl 3): b ppm 2.92 (s, ZN), 3.16 (s, ZN), 5.565.58 (m, 1H), 6.73 (d, J = 8.0 Ηζ, 1H), 7.59 dd, J = 4.8, 1.6 Ηζ, 2H), 8.30 (d, J = 8.0 Ηζ, 1H), 8.74 (dd, J = 4.8, 1.6 Ηζ, 2H).

137

<img file="RS54504B1_D0069.tif" />

54504 Β1

Reference example 45

- [(2-Chlorophenyl) hydrazone] pentane-2,4-dione

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

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.64 (s, ZN), 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-Chlorophenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0070.tif" />

Dissolve 3 - [(2-chlorophenyl) hydrazono] pentane-2,4-dione (500 mg, 2.10 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h, it was then concentrated under reduced pressure to give crude 1- (2-chlorophenyl) -3- [3 (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which was used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, CDCl 3): δ ppm 2.90 (s, ZN), 3.12 (s, ZN), 5.565.59 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 7.42- 7.45 (m, 2 H), 7.52-7.57 (m, 2 H), 7.91 (d, J = 8.0 Hz, 1 H).

138

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<img file="RS54504B1_D0071.tif" />

Reference example 47

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

A solution of 3- (methylsulfanyl) aniline (13.9 g, 100 mmol) in hydrochloric acid (6 M, 100 mL) was cooled in an ice bath and treated dropwise with a solution of sodium nitrite (8.38 g, 121 mmol) in water (25 mL). ), maintaining a temperature between -5 ° C and 5 ° C. A solution of diazonium formed in situ was rapidly 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 below 0 °. C. After stirring at 0 ° C for 30 min, this suspension was filtered, orege with water (40 mL) and evaporated with toluene to give 3 - {[3 (methylsulfanyl) phenyl] hydrazono} pentane-2,4-dione (23.10 g, 92 %) as a yellow-red solid.

¹1 H NMR (500 MHz, DMSO-d 6) δ ppm 2.43 (s, 6H), 2.47 (s, ZN), 7.04-7.06 (m, 1H), 7.31-7.36 (m, 2H), 7.46 (s, 1H) , 13.80 (brs, 1 H);

APCI MS m / z 251 [M⁺ H]⁺.

Reference example 48

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

<img file="RS54504B1_D0072.tif" />

<img file="RS54504B1_D0073.tif" />

A mixture of 3 - {[3- (methylsulfanyl) phenyl] hydrazono} pentane-2,4-dione (14.9 g, 59.6 mmol) in N, N-dimethylformamide dimethylacetal (70 mL) was stirred at 125 ° C for 2.5 h. Thereafter, this reaction was directly concentrated and dissolved in methanol (80.0 mL). After concentration, the crude product is purified by flash chromatography (silica gel, methylene chloride to 95: 5 methylene chloride / methanol) to give 3- [3- (dimethylamino) prop-2-enoyl] 139

54504 Β1

1- [3- (methylsulfanyl) phenyl] pyridazin-4 (1H) -one (16.3 g, 87%) as a tan solid.

¹1 H NMR (500 MHz, DMSO-d 6) δ 2.54 (s, ZN), 2.83 (s, ZN), 3.09 (s, ZN), 5.23 (br s, 1H), 6.53 (d, J = 8.0 Ηζ, 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

<img file="RS54504B1_D0074.tif" />

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 h. Thereafter, the reaction was directly concentrated to remove methanol and then dissolved in methylene chloride (100 mL). This solution was stirred with 2 M hydrogen chloride (60 mL), water (60 mL) and brine (60 mL). After concentration, this 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-pyrazol-5-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 regiomer ratio of about 1: 1, as a white solid.

¹1 H NMR for 2 isomers (500 MHz, DMSO-d 6)₆) 6 ppm 6.63 (d, J = 8.0 Ηζ, 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, ZN), 7.59 (d, J = 9.3 Hz, 1H), 7.68 (s, 1H), 7.82 (d, J = 1.7 Ηζ, 1H), 7.92 (d, J = 7.8 Ηζ, 2H), 8.59 (d, J = 2.4 Ηζ, 1H), 8.84 (d, J = 8.0 Ηζ, 1H), 8.89 (d, J = 7.9 Hz, 1H); APCI MS m / z 361 [M + H]⁺.

Reference example 50

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

140

54504 Β1

<img file="RS54504B1_D0075.tif" />

A solution of 3-aminophenol (5.16 g, 47.3 mmol) in tetrafluoroboronic acid (30 mL, 50% in water) was cooled in an ice bath and treated dropwise with sodium nitrite (3.92 g, 56.8 mmol) in water. ), maintaining the bathroom temperature between -5 ° C and 5 ° C. A rapidly formed in situ solution of diazonium was 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), below 0 ° C. . After stirring for 30 min at 0 ° C, this suspension was filtered, washed with water (70 mL) and evaporated with toluene to give 3 - [(3-hydroxyphenyl) hydrazono] pentane-2,4-dione (5.85 g, 56%). a brick-colored solid.

¹1 H NMR (500 MHz, DMSO-d 6) 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, 1 H); ESI MSm / z 221 [M + H]⁺.

Reference Example 51 3- [3- (Dimethylamino) prop-2-enoyl] -1- (3-hydroxyphenyl) pyridazin-4 (1H) -one

HO '

<img file="RS54504B1_D0076.tif" />

A mixture of 3 - [(3-hydroxyphenyl) hydrazono] pentane-2,4-dione (2.02 g, 9.18 mmol) in N, N-dimethylformamide dimethyl acetal (20 mL) was stirred for 1 h at 100 ° C. Thereafter, the reaction was concentrated directly and then dissolved in methanol (60 mL). After evaporation with silica gel, this 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.

¹1 H NMR (500 MHz, DMSO-d 6) δ ppm 2.83 (s, ZN), 3.09 (s, ZN), 5.21-5.23 (m, 1H),

6.50 (d, J = 8.0 Hz, 1 H), 6.79-6.82 (m, 1 H), 7.08-7.11 (m, 2 H), 7.33 (t, J = 8.1 Hz, 1 H), 8.74 (d, J = 8.0 Hz) , 1H), 9.93 (s, 1H);

141

54504 Β1

ESI MS m / z 286 [M⁺ H]⁺.

Reference example 52

1- (3-Hydroxyphenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0077.tif" />

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 h. Thereafter, the reaction was directly concentrated to remove methanol and then dissolved in methylene chloride (60 mL). This 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) pyridazin-4 1H) -one (0.360 g, 65%) as a brown-yellow solid.

¹1 H NMR (500 MHz, DMSO-d 6) δ ppm 6.63 (d, J = 7.8 Ηζ, 1H), 6.85 (d, J = 9.0 Hz, 1H), 7.21-7.23 (m, 2H), 7.35-7.39 (m , ZN), 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 Ηζ, 1H), 10.0 (s, 1 H); 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-phenyl-1H-pyrazol-3-yl) -1- (3-sulfanylphenyl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0078.tif" />

Solution of 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 (0.300 g, 0.83 mmol)

142

54504 Β1 and sodium t-butylthiolate (0.295 g, 2.63 mmol) in DMF (6 mL) was heated at 170 ° C in an airtight vessel for 2.5 days. Thereafter, the reaction was cooled to room temperature and diluted with water (60 mL). HCl in water (1 M, 2 mL, 2 mmol) was added and the reaction was extracted with ethyl acetate (2 χ 80 mL). The combined organic phases were washed with 5% aqueous LiCl solution (100 mL) and saturated aqueous NaCl solution (80 mL). The organic phase was dried (MgSO 4) and concentrated to give a mixture of the title compounds as a brown gum (0.325 g). LCMS analysis of the reaction products showed the presence of 2 isomeric products of this thiol, obtained in the ratio = 1.5: 1. This crude product was used in the next 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-ylsulfanyl) phenyl] -3- (1-phenyl-1H-pyrazol-3-yl) pyridazin-4 (1H) -one

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- (3-sulfanylphenyl) 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) were heated at 170 ° C in a sealed vessel for 24 h. Thereafter, the reaction was cooled to room temperature and diluted with water (50 mL). HCl in water (2 M, 0.800 mL, 1.60 mmol) was added and the reaction was extracted with ethyl acetate (3 x 60 mL). The combined organic phases were prepared with 5% aqueous LiCl solution (100 mL) and saturated aqueous NaCl solution (100 mL). The organic phase was dried (MgSO 4) and concentrated to a brown solid (0.312 g). This crude product was used in the next reaction without further purification or characterization.

Reference example 55

Methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazono} butanoate

143

54504 Β1

<img file="RS54504B1_D0079.tif" />

A thick suspension of 3- (trifluoromethyl) aniline (16.12 g, 100 mmol) in 6 M HCl (100 mL) was cooled to 0 ° C and treated dropwise with a solution of sodium nitrite (8.33 g, 121 mmol) in water (20 mL). The resulting light yellow solution was poured into a thick 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 thick orange suspension was stirred for 10 min. Thereafter, the product was collected by filtration and washed with water (500 mL). This crude material was dissolved in ethyl acetate (250 mL) and dried (Md2Od). The product crystallized after concentrating ethyl acetate to give 19.997 g (69%) of methyl 3-oxo-2 - {[3 (trifluoromethyl) phenyl] hydrazono} butanoate as light yellow crystals.

¹1 H NMR (300 MHz, CDCl 3) showed a mixture of isomers. Major isomer b ppm 2.62 (s, ZN), 3.90 (s, ZN), 7.37-7.45 (m, 1H), 7.46-7.54 (m, 1H), 7.58 (s, 1H), 7.67 (s, 1H), 14.76 (br s, 1 H); Minor isomer b ppm 2.52 (s, ZN), 3.93 (s, ZN), 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 [CuHuFaNzCh * H]⁺.

Reference example 56

Methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate

<img file="RS54504B1_D0080.tif" />

A solution of methyl 3-oxo-2 -} [3- (trifluoromethyl) phenyl] hydrazono} butanoate (15.20 g, 52.7 mmol) in N, N-dimethylformamide dimethyl acetal (150 mL) was heated at reflux for 2 h. After that, the reaction was cooled to room temperature and then in a bath of ice and water. The product was collected by filtration to give methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (13.7 g, 87%) as light yellow crystals.

¹1 H NMR (300 MHz, CDCl 3) δ ppm 4.00 (s, ZN), 6.80 (d, J = 8.1 Hz, 1H), 7.61-7.76 (m, 2H), 7.76-7.91 (m, 2H), 8.28 , J = 8.1 Hz, 1H);

144

54504 Β1

APCI MS m / z 299 [CnHsFsNsOs * H]⁺.

Reference example 57

4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbohydrazide

<img file="RS54504B1_D0081.tif" />

NHNHj

A solution of methyl 4-oxo-143 ”(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 at 120 ° C for 10 min. Thereafter, the reaction 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%). , like shiny orange crystals.

¹1 H NMR (300 MHz, CDCl 3) 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 [C 12 H 9 F 3 N 4 O 2 + hP⁺.

Reference example 58

4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0082.tif" />

A solution of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (1,007 g, 3.38 mmol) in ammonia (7 M in MeOH, 12 mL, 84 mmol) was heated under microwave conditions at 100 ° C for 5 min. The reaction was then cooled to room temperature and concentrated to give a yellow solid. This was recrystallized from EtOAc to give 0.613 g (64%) of 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide as colorless crystals.

145

54504 Β1 ¹1 H NMR (300 MHz, CDCl 3) δ ppm 6.46 (br s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 7.59-7.80 (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

Thick suspension

<img file="RS54504B1_D0083.tif" />

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 conditions to 130 ° C for 15 minutes. min. The reaction was then cooled in an ice-water bath, and the resulting crystals were collected by filtration and washed with hexanes to give 0.491 g (76%) of N - [(dimethylamino) methylidene] -4-oxo-1- [3 (trifluoromethyl) phenyl ] -1,4-Hydropyridazine-3-carboxamide as an off-white crystal.

¹1 H NMR (300 MHz, CDCl 3) δ ppm 3.16 (s, ZN), 3.22 (s, ZN), 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&gt;, 8.70 (s, 1H).

Reference example 60

4-Oxo-N-phenyl-1- [3 ”(trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0084.tif" />

A solution of aniline (0.360 mL, 3.95 mmol) in methylene chloride (10 mL) was cooled in an ice and water bath and then treated with a solution of trimethyl aluminum (2 M in toluene, 2.0 mL, 4.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. Then methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (0.595 g, 2.00 mmol) was added and the reaction was heated

146

54504 Β1 under reflux for 18 h. Thereafter, the reaction was cooled to room temperature and carefully treated with a solution of HCl in water (1 M, 5 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3 x 10 mL). The combined organic extracts were washed with saturated aqueous №NSO 2 (50 mL) and brine (50 mL), dried (MgSO 4) and concentrated. The residue was recrystallized from ethyl acetate / hexane to give 0.214 g (30%) of 4-oxo-N-phenyl-1- [3- (trifluoromethyl) phenyl] -1._l4-dihydropyridazine-3-carboxamide as yellow crystals.

¹1 H NMR (300 MHz, CDCl 3) δ ppm 6.96 (d, J = 7.7 Ηζ, 1H), 7.16 (t, J = 7.4 Ηζ, 1H), 7.37 (t, J = 7.9 Ηζ, 2H), 7.61-7.85 m, 4H), 7.88-8.01 (m, 2H), 8.42 (d, J = 7.8 Hz, 1H), 12.19 (brs, 1H);

APCI MS m / z 360 [M + H]⁺; temp.toplj. 181-182 ° C.

Reference example 61

3- [1H-Benzotriazol-1-yl (phenylimino) methyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0085.tif" />

4-Oxo-N-phenyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide solution (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) were heated under microwave conditions, at 80 watts of power, for 10 min. Thereafter, the reaction was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes and ethyl acetate) to give 0.114 g (58%) of 3- [1H-benzotriazol-1-yl (phenylimino) methyl] -1- [3 - (trifluoromethyl) phenyl] pyridazin-4 (1H) -one as a light red solid, which is used without further characterization.

Reference example 62

3 - [(4-Piperidin-1-ylphenyl) hydrazone] pentane-2,4-dione

147

54504 Β1 ο ο · * ν VDe

<img file="RS54504B1_D0086.tif" />

4-Piperidin-1-ylaniline (510 mg, 2.90 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrite (200 mg, 2.90 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then 250 mL of a saturated solution of IagSO 2 in water was added, extracted with dichloromethane, oregeo water and brine, dried over MagbSi and concentrated under reduced pressure to give 3 [(4-piperidin-1-ylphenyl) hydrazone]. pentane-2,4-dione (570 mg, 68% yield).

LCMS: m / z = 288 [M⁺+ H].

Reference example 63

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

<img file="RS54504B1_D0087.tif" />

Dissolve 3 - [(4-piperidin-1-ylphenyl) hydrazono] pentane-2,4-dione (570 mg, 1.99 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and mix this reflux for 4 h, then concentrate under reduced pressure to give crude 3- [3- (dimethylamino) prop-

2-enoyl] -1- (4-piperidin-1-ylphenyl) pyridazin-4 (1H) -one, which was used in the next step without further purification.

Reference example 64

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

148

54504 Β1

<img file="RS54504B1_D0088.tif" />

To a solution of 4-cyclohexylaniline (500 mg, 2.86 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrogen chloride solution, sodium nitrite (237 mg, 3.43 mmol) in 4 mL of water was added dropwise at 0 ° C, so this mixture was stirred at 0 ° C for 1 h. A solution of sodium acetate (703 mg, 8.58 mmol) and acetylacetone (372 mg, 3.72 mmol) in 10 mL of ethanol and 6 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / NgO (1: 1) and hexane and dried to give 3 - [(4-cyclohexylphenyl) hydrazono] pentane-2,4-dione (420 mg, 51%).

¹1 H NMR (400 MHz, CDCl 3)₃): b ppm 1.24-1.27 (m, 2H), 1.38-1.43 (m, 4H), 1.85-1.87 (m, 4H), 2.49-2.52 (m, 4H), 2.60 (s, ZN), 7.25 (d , J = 8.4 Ηζ, 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

Dissolve 3 - [(4-cyclohexylphenyl) hydrazono] pentane-2,4-dione (406 mg, 1.42 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. it is then concentrated under reduced pressure to give crude 1- (4-cyclohexylphenyl) -3- [3- (dimethylamino) prop-2-enoyl] pyridazin-4 (1H) -one, which is used in the next step without further purification.

¹1 H NMR of the crude product (400 MHz, CDCl 3): δ ppm 1.25-1.28 (m, 2H), 1.39-1.44 (m, 4H), 1.86-1.88 (m, 4H), 2.52-2.54 (m, 1H), 2.90 (s, ZN), 3.13 (s, ZN), 5.62-5.64 (m, 1H), 6.71 (d, J = 7.6 Ηζ, 1H), 7.32 (d, J = 8.8 Ηζ, 2H), 7.49 (d, J = 8.8 Ηζ, 2H), 8.17 (d, J = 8.0 Ηζ, 1H).

149

54504 Β1

Reference example 66

4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzonitrile

<img file="RS54504B1_D0089.tif" />

<img file="RS54504B1_D0090.tif" />

4-Aminobenzonitrile (500 mg, 4.24 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrite (292 mg, 4.24 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This mixture was added, at 0 ° C, to a suspension of the corresponding 2,4-pentanedione (424 mg, 4.24 mmol) and potassium acetate (20 g) in ethanol (250 mL). This solution was stirred for 15 min, added to 250 mL of saturated aqueous MagSO 2, extracted with dichloromethane, oregeo water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 4 [2- (1-acetyl-2-oxopropylidene). ) hydrazino] benzonitrile (280 mg, 29%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.63 (s, ZN), 7.47 (dd, J = 7.2, 1.6 Hz, 2H), 7.70 (dd, J = 7.2, 1.6 Hz, 2H), 14.51 (s, 1 H).

Reference example 67

4- {3- [3- (Dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzonitrile

<img file="RS54504B1_D0091.tif" />

<img file="RS54504B1_D0092.tif" />

CN

Dissolve 4- [2- (1-acetyl-2-oxopropylidene) hydrazino] benzonitrile (266 mg, 1.16 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. , then concentrated under reduced pressure to give crude 4- {3- [3 (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) yl} benzonitrile, which was used in the next step without further purification.

150

54504 Β1 ¹Η Crude product NMR (400 MHz, CDCl 3): b ppm 2.96 (s, ZN), 3.20 (s, ZN), 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- (Methylsulfonyl) phenyl] hydrazono} pentane-2,4-dione

<img file="RS54504B1_D0093.tif" />

4- (methylsulfonyl) aniline (500 mg, 2.92 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), then -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and solid sodium nitrite (201 mg, 2.92 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of a saturated solution of №2SO2 in water, 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%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.63 (s, ZN), 3.08 (s, ZN), 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) -one

<img file="RS54504B1_D0094.tif" />

Dissolve 3 - {[4- (methylsulfonyl) phenyl] hydrazono} pentane-2,4-dione (500 mg, 1.77 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture. 4 h, then concentrated under reduced pressure to give crude 3- [3

151

54504 Β1 [(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] hydrazono} pentane-2,4-dione

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 this mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrite (85 mg, 1.24 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of saturated №2SO 2 solution, extracted with dichloromethane, washed with water and brine, dried over Na 2 SO 2 and concentrated under reduced pressure to give 3 {[4- (morpholin-44-sulfonyl) phenyl] hydrazone}. pentari ”2,4-dione (375 mg, 86%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.53 (s, ZN), 2.64 (s, ZN), 3.03 (t, J = 4.8 Ηζ, 4H), 3.76 (t, J = 4.8 Ηζ, 4H), 7.54 (dd, J = 7.2, 2.0 Ηζ, 2H), 7.80 (d, J = 8.8 Ηζ, 2H), 14.56 (s, 1H).

Reference example 71

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

<img file="RS54504B1_D0095.tif" />

Dissolve 3 - {[4- (morpholin-4-ylsulfonyl) phenyl] hydrazono} pentane-2,4-dione (300 mg, 0.85 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), then this mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3- [3

152

54504 Β1 [(dimethylamino) prop-2-enoyl] -1- [4- (morpholin-4-ylsulfonyl) phenyl] pyridazin-4 (1 Η) -οη, which was used in the next step without further purification.

Reference example 72

4- [2- (1-Acetyl-2-oxopropylidene) hydrazino] benzamide

4-Aminobenzamide (1000 mg, 7.36 mmol) was added to a solution of 6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature it was cooled to -6 ° C and solid sodium nitrite (508 mg, 7.36 mmol) was added over 10 min. Crushed ice (100 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of a saturated solution of IagSO 2 in water, extracted with dichloromethane, washed with water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 4 [2- (1-acetyl-2-oxopropylidene). hydrazino] benzamide (460 mg, 25%).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.52 (s, ZN), 2.62 (s, ZN), 7.46 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 14.62 (s, 1 H).

Reference example 73

4- {3- [3- (Dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzamide

Dissolve 4- [2- (1-acetyl-2-oxopropylidene) hydrazino] benzamide (540 mg, 2.19 mmol) in 10 mL of N, N-dimethylformamide dimethylacetal (DMF-DMA), and reflux this mixture for 4 h. , then concentrated under reduced pressure to give crude 4- {3- [3 (dimethylamino) prop-2-enoyl] -4-oxopyridazin-1 (4H) -yl} benzamide, which was used in the next step without further purification.

153

54504 Β1 ¹Η Crude product NMR (400 MHz, CDCl 3): b ppm 2.91 (s, ZN), 3.14 (s, ZN), 5.605.62 (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] hydrazono} pentanoate

<img file="RS54504B1_D0096.tif" />

A thick suspension of 3- (trifluoromethyl) aniline (8.03 g, 50 mmol) in 6 M HCl (50 mL) was cooled to 0 ° C and treated dropwise with a solution of sodium nitrite (4.10 g, 60 mmol) in water. 10 mL). The resulting light yellow solution was poured into a suspension of methyl propionylacetate (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 slurry was stirred for 30 min. The product was collected by filtration and dried with water (100 mL). This crude material was dissolved in ethyl acetate (100 mL) and dried (MagbOd). The product crystallized after concentration in ethyl acetate to give (14.00 g, 93%) methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazono} pentanoate as a yellow-orange solid.

¹1 H NMR (500 MHz, CDCl 3) indicated a mixture of isomers. Major isomer: b ppm 1.18 (t, J = 7.5 Hz, ZN), 2.96 (q, J = 7.5 Hz, 2H), 3.92 (s, ZN), 7.39-7.42 (m, 1H), 7.48-7.55 , 2H), 7.56 (s, 1H), 12.75 (br s, 1H); Minor isomer: b ppm 1.15 (t, J = 7.5 Hz, ZN), 3.04 (q, J = 7.5, 2H), 3.90 (s, ZN), 7.39-7.42 (m, 1H), 7.48-7.55 (m, 2H), 7.67 (s, 1 H), 14.76 (br s, 1 H);

ESI MS m / z 303 [M + H]⁺.

Reference example 75

Methyl 5-methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate

154

54504 Β1

A solution of methyl 3-oxo-2 - {[3- (trifluoromethyl) phenyl] hydrazono} pentanoate (4.00 g, 13.2 mmol) in N, N-dimethylformamide dimethyl acetal (33 mL) was heated at reflux for 2.5 h. Thereafter, the reaction was cooled to room temperature, and the resulting precipitate was collected by filtration and the walnut with a small volume of hexane to give methyl 5-methyl-4-oxo-1- [3 (trifluoromethyl) phenyl] -1,4-dihydropyridazin-3 -carboxylate (3.55 g, 87%) as a light yellow solid.

¹1 H NMR (500 MHz, CDCl 3) δ ppm 2.19 (s, ZN), 4.00 (s, ZN), 7.65-7.71 (m, 2H), 7.817.85 (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

To a stirred suspension of NO-dimethylhydroxylamine hydrogen chloride (0.468 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise trimethyl aluminum (2.4 mL, 4.8 mmol, 2 M toluene solution), at 0 ° C. After the addition was complete, this suspension was stirred for 10 min at 0 ° C and then for 30 min at room temperature to give a homogeneous solution. The balloon is then cooled again 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) was dissolved in dichloromethane (5 mL) and added. in drops and allowed to stir for 2 h. The reaction was treated with water (5 mL) and 2 M solution of HCl in water (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- [3- (trifluoromethyl) phenyl] -1, 4-Dihydropyridazine-3-carboxamide (0.535 g, 98%) as a yellow solid.

¹1 H NMR (500 MHz, CDCl 3) δ ppm 2.18 (s, ZN), 3.41 (s, ZN), 3.68 (s, ZN), 7.63-7.70 (m, 2H), 7.80-7.90 (m, 2H), 8.21 (s, 1 H);

APCI MS m / z 342 [M + H]⁺.

155

54504 Β1

Reference example 77

3-Acetyl-5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0097.tif" />

To a solution of N-methoxy-N, 5-dimethyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine3-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 was stirred at that temperature for 1 h, then treated with a saturated solution of ammonium chloride in water (5 mL), then water (2 mL), gradually 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 * 10 rmL), and the combined organic extracts were washed with 1 M aqueous HCl (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated to give 3- acetyl-5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) one (0.463 g, 98%) as a light yellow solid.

¹1 H NMR (500 MHz, CDCl 3) δ ppm 2.19 (s, ZN), 2.69 (s, ZN), 7.67-7.72 (m, 2H), 7.827.85 (m, 2H), 8.21 (s, 1H);

APCI MSm / z297 [M + H]⁺.

Reference Example 78 3- [3- (Dimethylamino) prop-2-enoyl] -5-methyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0098.tif" />

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 dimethylacetal (2.5 mL), heat at 120 ° C for 20 min. 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.

156

54504 Β1 ¹Η NMR (300 MHz, CDCl 3) δ ppm 2.18 (s, ZN), 2.92 (s, ZN), 3.14 (s, ZN), 5.69-5.82 (m, 1H), 7.63-7.65 (m, 2H), 7.83 -7.87 (m, ZN), 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

A thick suspension of 3-acetyl-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (0.369 g, 1.30 mmol) in N, N-dimethylacetamide-dimethylacetal (3.5 mL, 18.3 mmol) was heated under microwave conditions for 5 min at 120 ° C. After that, the reaction was cooled to room temperature and concentrated with 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.

¹1 H NMR (500 MHz, CDCl 3) δ ppm 2.71 (s, ZN), 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-fluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate

A solution of NaNCl (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 solution of HCl in water (20 mL, 120 mmol). ). After stirring for 15 min, 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. This reaction mixture was poured into water, well

157

54504 Β1 extracted with AcOEt. This extract was dried with saturated aqueous MaNSO 2 and brine, dried over MgSO 3 and concentrated under reduced pressure. The residue was recrystallized from hexane / AcOEt to give the title compound (5.03 g, 94% yield) as light yellow crystals: m.p. 121-126 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.51 (ZN, s), 3.94 (ZN, s), 4.68 (2H, s), 7.08-7.25 (ZN, m), 7.63 (1H, dt, J = 1.5 , 7.9 Hz), 13.06 (1H, brs).

Analysis: Calculation. 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-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

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 refluxed for 1 h. 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.91 (ZN, s), 3.97 (ZN, 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. Calculation. for C13H11FN2O4: C, 56.12; H, 3.98; N, 10.07. Found: C, 56.17; H, 3.97; N, 10.25.

Reference example 82

1- (2-Fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (4.74 g, 48.6 mmol) and iPrsNEt (8.47 ml, 48.6 mmol) in CH2Cl2 (50 mL) was added dropwise A1Mez (1.8 M solution in

158

54504 Β1 toluene, 27 mL, 48.6 mmol), at 0 ° C, under an Ag atmosphere. After stirring for 1 h, 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 this mixture was stirred at 0 ° C for 1 h. The reaction mixture was poured into ice-water, acidified with 1 M aqueous HCl, saturated with NaCl and extracted five times with AcOEt. The combined extracts were dried over MgSO 4 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.39 (ZN, s), 3.71 (ZN, s), 3.91 (ZN, 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. Calculation. for CuHuFNaCu: 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

MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at -78 ° C to the solution.

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 h, the reaction mixture was treated with 1 M aqueous HCl, saturated with NaCl and extracted five times with AcOEt. The combined extracts were dried over MgSO 4 and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (2.32 g, 85% yield) as light yellow crystals: m.p. 154-156 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.69 (ZN, s), 3.91 (ZN, 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. Calculation. 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

159

54504 Β1

ΙΜ.-Ν

<img file="RS54504B1_D0099.tif" />

A solution of NaNCte (2.378 g, 34.5 mmol) in NgO (10 mL) was added dropwise, at 0 ° C, to a solution of 2- (difluoromethoxy) aniline (3.59 mL, 28.7 mmol) in a 6 M solution of HCl in water (28.7 mL). , 172 mmol). After stirring for 15 min, 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. This precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was washed with water, brine and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was stirred with hexane / AcOEt (3/1) to give the title compound (8.70 g, 96% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.51 (ZN, s), 3.89 (ZN h 0.5, s), 3.94 (ZN χ 0.5, s), 4.68 (1H χ 0.5, s), 4.70 (1Η χ 0.5) , s), 6.63 (1Η χ 0.5, t, J = 72.7 Hz), 6.66 (1Η h 0.5, t, J = 72.3 Hz), 7.10-7.34 (4H, m), 7.67 (1Η 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

A solution of methyl 2 - {[2- (difluoromethoxy) phenyl] hydrazono) ~ 4-methoxy-3-oxobutanoate (8.70 g, 27.5 mmol) in N, N-dimethylformamide dimethylacetal (60 mL) was refluxed for 3 h, then 3 days stirred at room temperature. 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:

¹1 H NMR (300 MHz, CDCl 3): δ pprm 3.89 (ZN, s), 3.96 (ZN, s), 6.55 (1H, d, J = 72.7 Hz), 7.35-7.45 (2H, m), 7.49-7.56 1 H, m), 7.61 (1 H, dd, J = 7.9, 1.5 Hz), 7.73 (1 H, s).

Reference example 86

160

54504 Β1

1- [2- (Difluoromethoxy) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

Meo ^ Dd,. Me uG ό_Μβτύ

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (5.27 g, 54.0 mmol) and iPf2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added dropwise A1Mez (1.8 M solution in toluene, 30.0 mL, 54.0 mmol). ), at 0 ° C. After stirring at 0 ° C for 1 h, a solution of methyl 1- [2- (difluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5.87 g, 17.99 mmcl) in CH2Cl2 was added dropwise. (60 mL), and this mixture was stirred at 0 ° C for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. This extract was digested with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was stirred with hexane / AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.38 (ZN, s), 3.68 (ZN, s), 3.89 (ZN, 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

<img file="RS54504B1_D0100.tif" />

MeMgBr (1 M solution in THF, 40.4 mL, 40.4 mmol) was added dropwise, followed by -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 h, the reaction mixture was treated with a 1 M solution of HCl in water and warmed to room temperature. The reaction mixture was concentrated under reduced pressure and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / AcOEt (1 / 1-0 / 1) and recrystallized from the mixture.

161

54504 Β1 diisopropyl ether / AcOEt to give the title compound (3.33 g, 80% yield) as colorless crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.68 (ZN, s), 3.89 (ZN, s), 6.55 (1H, t, J = 72.7 Hz), 7.36-7.45 (2H, m), 7.50 - 7.57 1 H, m), 7.61 (1 H, dd, J = 7.8, 1.7 Hz), 7.72 (1 H, s).

Reference example 88

1- [2- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazin-4 (1H) one

Mixture of 3-acetyl-1- [2- (difluoromethoxy) phenyl] -5-methoxypyridazin-4 (1H) -one (3.70 g,

11.93 mmol) and N, N-dimethylformamide dimethylacetal (50 mL) was refluxed for 5 h and stirred overnight at room temperature. The precipitate was collected by filtration and dried with AcOEt to give the title compound (4.07 g, 93% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.90 (ZN, s), 3.12 (ZN, br s), 3.87 (ZN, 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

A solution of NaNCl (4.14 g, 60 mmol) in NgO (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. , 300 mmol). After stirring for 15 min, 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 to 0 ° C. This precipitate was collected by filtration, germinated with water and dissolved in AcOEt. The organic solution is dried with water and brine, dried

162

54504 Β1 above Na2SO4 and concentrates under reduced pressure. The residue was crystallized from hexane / AcOEt to give the title compound (14.0 g, 88% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.51 (ZN χ 0.36, s), 3.52 (ZN χ 0.64, s), 3.90 (ZN χ 0.36, s), 3.94 (ZN χ 0.64, s), 4.68 (2H) χ 0.64, s), 4.70 (2Η χ 0.36, s), 7.41-7.59 (ZN + 1H χ 0.64, m), 7.71 (1Η χ 0.36, s), 13.00 (1Η χ 0.64, s), 14.87 (1Η χ) 0.36, s).

Reference example 90

Methyl 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate

A solution of methyl 4-methoxy-3-oxo-2 - [[3- (trifluoromethyl) phenyl] hydrazono} butanoate (14.0 g, 44 mmol) in N, N-dimethylformamide dimethyl acetal (100 mL) was refluxed for 4 h. at 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: mp 169-170 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.98 (ZN, s), 3.99 (ZN, s), 7.66-7.74 (2H, m), 7.83-7.89 (2H, m), 7.95 (1H, s).

Anal. Calculation. for C14H11F3N2O4: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.15; H, 3.47 N, 8.60.

Reference Example 91 N, 5-Dimethoxy-N “methyl-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxamide

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (2.63 g, 27 mmol) and iPrsNEt (4.70 mL, 27 mmol) in CH 2 Cl 2 (30 mL) was added dropwise A 1 Mez (1.8 M solution in toluene, 15 mL, 27 mmol), 0 ° C, under an atmosphere of Ag. After stirring for 1 h, it is added dropwise

163

54504 Β1 solution of methyl 5-methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (2.95 g, 9 mmol) in CH 2 Cl 2 (30 mL), and this mixture was stirred for 1 h at 0 ° C. The reaction mixture was poured into ice-water and extracted with AcOEt. This extract was digested 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 (2.15 g, 67% yield) as off-white crystals: m.p. 170-171 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.41 (ZN, s), 3.71 (ZN, s), 3.98 (ZN, s), 7.63-7.71 (2H, m), 7.80-7.86 (1H, m), 7.88 (1 H, s), 7.98 (1 H, s).

Anal. Calculation. 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

<img file="RS54504B1_D0101.tif" />

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 h, the reaction mixture was treated with saturated aqueous NH4Cl and extracted three times with AcOEt. The combined extracts were washed with brine, dried over Md3Od and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, 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: m.p. 155-156 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.71 (ZN, s), 3.98 (ZN, s), 7.68-7.76 (2H, m), 7.83-7.88 (2H, m), 7.94 (1H, s).

Anal. Calculation. 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

164

54504 Β1

<img file="RS54504B1_D0102.tif" />

NMe_a

A solution of 3-acetyl-5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (1.39 g, 4.45 mmol) in N, N-dimethylformamide dimethyl acetal (15 mL) was refluxed for 3 h. . 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 four times with AcOEt. The combined organic layers were dried over MgSO 4 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.91 (ZN, s), 3.14 (ZN, s), 3.96 (ZN, 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. Calculation. 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

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 HCl. mL, 120 mmol). After stirring for 15 min, 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 added to water and extracted with AcOEt. This extract was washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 3 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;

165

54504 Β1 ¹Η NMR (300 MHz, CDCl 3): δ ppm 3.50 (ZN, s), 3.93 (ZN, 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. Calculation. 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

A solution of methyl 2 - [(2-fluoro-4-iodophenyl) hydrazono] -4-methoxy-3-oxobutanoate (6.27 g, 15.9 mmol) in N, N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This extract was digested with water and brine, dried over MgSO 3 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.90 (ZN, s), 3.97 (ZN, s), 7.36-7.41 (1H, m), 7.64-7.70 (2H, m), 7.73 (1H, d, J = 2.6 Hz).

Anal. Calculation. for C13H10OFI0₄Stk #: C, 38.64; H, 2.49; N, 6.93. Found: C, 38.68; H, 2.59; N, 6.98.

Reference Example 96 1- (2-Fluoro-4-iodophenyl) -N, 5-dimethoxy-N-nethyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (8.78 g, 90 mmol) and iPr2NEt (15.7 mL, 90 mmol) in CH2Cl2 (100 mL) was slowly added dropwise AI Mez (1.8 M solution in

166

54504 Β1 toluene, 50 mL, 90 mmol), at 0 ° C, under Ar. After stirring for 1 h, a solution of methyl 1- (2-fluoro-4-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (12.1 g, 30 mmol) in CH 2 Cl 2 (100 mL) was added slowly. , and this mixture was stirred at 0 ° C for 1 h. The reaction mixture was poured into an ice-water mixture 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 chromatography, eluting with silica gel, eluting with AcOEt to give the title compound (9.96 g, 77% yield) as a white amorphous substance.

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.39 (ZN, s), 3.70 (ZN, s), 3.90 (ZN, s), 7.39 (1H, t, J = 8.1 Hz), 7.63-7.67 (2H, pp), 7.77 (1H, d, J = 2.3 Hz).

Reference example 97

3-Acetyl I-1- (2-fluoro-4-iodophenyl) -5-methoxypyridazin-4 (1H) -one

<img file="RS54504B1_D0103.tif" />

i

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-dihydropindazine-3-carboxamide (9.96 g, 23 mmol) in THF (250 mL). After stirring for 1 h, the reaction mixture was treated with 1 M aqueous HCl and extracted with AcOEt. This extract was digested with brine, dried over MdbOd and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and recrystallized from MeOH to give the title compound (2.05 g, 23% yield) as light yellow crystals: m.p. 196-198 ° C.

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.67 (ZN, s), 3.90 (ZN, s), 7.36-7.41 (1H, m), 7.66-7.71 (2H, m), 7.73 (1H, d, J) = 2.6 Hz).

Anal. Calculation. 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

167

54504 Β1

<img file="RS54504B1_D0104.tif" />

A solution of NaNO2 (2.48 g, 36 mmol) in NgO (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. , 180 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 5-methoxy-3-oxovalerate (4.37 mL, 30 mmol) and NaOAc (14.8 g, 180 mmol) in EtOH (50 mL), pre-cooled to 0 ° C. After stirring for 5 min, the reaction mixture was poured into water and extracted with AcOEt. This extract was washed with saturated NaHCO solution₃ in water and brine, dried over MgSO4 and concentrated under reduced pressure.

A solution of this residue in N, N-dimethylformamide dimethyl acetal (50 mL) was refluxed for 4 h. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from AcOEt to give the title equation (7.13 g, 69% yield) as a yellow solid: m.p. 138-140 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.53 (ZN, s), 4.00 (ZN, s), 4.49 (2H, d, J = 1.5 Hz), 7.65-7.73 (2H, m), 7.82-7.85 ( 1 H, m), 7.89 (1 H, s), 8.38 (1 H, t, J = 1.5 Hz).

Anal. Calculation. 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

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (2.63 g, 27 mmol) and iP ^ NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added dropwise A1Mez (1.8 M solution in toluene, 15 mL, 27 mmol), at 0 ° C, under an Ag. After stirring for 1 h, a solution of methyl 5- (methoxymethyl) -4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropindazine-3-carboxylate (3.08 g, 9 mmol) in CH2Cl2 was added dropwise. mL), and this mixture was stirred at 0 ° C for 1 h.

168

54504 Β1

The reaction mixture was poured into ice-water and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and recrystallized from hexane / AcOEt to give the title compound (1.99 g, 60% yield) as an off-white solid: mp. 157-169 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.41 (ZN, s), 3.53 (ZN, s), 3.67 (ZN, 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. Calculation. for C 11 H 11 FN 5 Cl 2: 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

<img file="RS54504B1_D0105.tif" />

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 h, the reaction mixture was treated with saturated aqueous NFkCl and extracted with AcOEt. This extract was washed with brine, dried over MdbOd and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and recrystallized from hexane / AcOEt to give the title compound (1.42 g, 83% yield) as a light yellow solid: m.p. 141-143 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.68 (ZN, s), 3.54 (ZN, s), 4.50 (2H, d, J = 1.5 Hz), 7.66-7.74 (2H, m), 7.81-7.87 ( 1 H, m), 7.89 (1 H, s), 8.38 (1 H, t, J = 1.5 Hz).

Anal. Calculation. 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

169

54504 Β1

<img file="RS54504B1_D0106.tif" />

<img file="RS54504B1_D0107.tif" />

A mixture of 3 - {[3- (trifluoromethyl) phenyl] hydrazono} 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 h. This mixture was diluted with 1 M aqueous HCl, extracted with EtOAc, orege brine, dried over NazSCl, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 80/20), then triturated with EtOAc / hexane to give the title compound (3.38 g, 65% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 2.55 (ZN, s), 6.75 (1H, d, J = 8.0 Hz), 7.787.88 (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

<img file="RS54504B1_D0108.tif" />

<img file="RS54504B1_D0109.tif" />

<img file="RS54504B1_D0110.tif" />

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 Vgg (0.181 mL, 3.54 mmol) at room temperature. . This mixture was stirred at room temperature for 2 h. This mixture was diluted with water and a solution of NaHCO3 in water, extracted with EtOAc, dried over MgSO 4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100) to give the title compound. mg, 26% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 2.57 (ZN, 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

170

54504 Β1

<img file="RS54504B1_D0111.tif" />

A solution of NaNO2 (2.07 g, 30 mmol) in NgO (10 mL) was added dropwise at 0 ° C to a mixture of 3- (trifluoromethyl) aniline (3.12 mL, 25 mmol) and 6 M aqueous HCl. , 150 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of dimethyl 1,3-acetonedicarboxylate (3.61 mL, 25 mmol) and NaOAc (12.3 g, 150 mmol) in EtOH (40 mL), pre-cooled to 0 ° C. After stirring for 10 min, the reaction mixture was poured into water and extracted with AcOEt. This extract was digested with a saturated solution of IaNSO 2 in water and brine, dried over MgSO 4 and concentrated under reduced pressure.

A solution of the residue and NaOMe (2.70 g, 50 mmol) in MeOH (50 mL) was stirred for 30 min at room temperature. The reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure.

A suspension of the residue, Mel (3.11 mL, 50 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF (50 mL) was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. This extract was digested with water and brine, dried over Md3Od and concentrated under reduced pressure. The residue was purified by basic chromatography followed by silica gel column, eluting with hexane / AcOEt (1/1) and recrystallized from hexane / AcOEt to give the title compound (1.83 g, 22% yield) as a light yellow solid. temp.toplj. 124-125 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.94 (ZN, s), 3.95 (ZN, 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. Calculation. 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

171

54504 Β1

<img file="RS54504B1_D0112.tif" />

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (1.58 g, 16.2 mmol) and iPr2NEt (2.82 mL, 16.2 mmol) in CH2Cl2 (13 mL) was added dropwise A1Mez (1.8 M solution in toluene, 9.0 ml_, 16.2 mmol). , at 0 ° C, in an atmosphere of Ar. After stirring for 1 h, a solution of methyl 4-methoxy-6-oxo-1- [3- (trifluoromethyl) phenyl] -1,6-dihydropyridazine-3-carboxylate (1.77 g, 5.4 mmol) in CH2Cl2 (15 mL) was added dropwise. , and this mixture was stirred at 0 ° C for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and crystallizing from hexane / AcOEt to give the title compound (1.48 g, 83% yield) as a white solid: mp. 127-129 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.37 (ZN, s), 3.64 (ZN, s), 3.91 (ZN, s), 6.30 (1H, s), 7.55-7.60 (1H, m), 7.62- 7.65 (1 H, m), 7.82-7.86 (1 H, m), 7.88 (1 H, s).

Anal. Calculation. 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

<img file="RS54504B1_D0113.tif" />

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 h, the reaction mixture was treated with saturated aqueous NH4Cl and extracted with AcOEt. This 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: mp. 136-138 ° C;

172

54504 Β1 ¹1 NMR (300 MHz, CDCl 3): δ ppm 2.57 (ZN, s), 3.93 (ZN, 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. Calculation. 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

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 refluxed for 3 h . After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. This residue was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure.

A solution of the residue and phenylhydrazine (0.551 mL, 5.19 mmol) in MeOH (5 mL) was refluxed.

h. After cooling to room temperature, the reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. This extract was digested 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 (323 mg, 45% yield) as a white solid: mp. 165-167 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.73 (ZN, 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. Calculation. 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

173

54504 Β1

<img file="RS54504B1_D0114.tif" />

<img file="RS54504B1_D0115.tif" />

he

<img file="RS54504B1_D0116.tif" />

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 a 1 M solution of NaOH in water (50 mL), at 0 ° C. This mixture was stirred at room temperature for 30 min. To this suspension was added a 1 M solution of HCl in water (50 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, germinated with water and dried under vacuum at 50 ° C to give the title compound (9.25 g, 97% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 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

<img file="RS54504B1_D0117.tif" />

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 at 40 ° C for 2 h. To this solution was added N-methoxymethanamine hydrogen chloride (1.03 g, 10.6 mmol) and i-Pr2NEt (1.84 mL, 10.6 mmol), at room temperature. This solution was stirred at room temperature for 20 h. This mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO₄, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 80/20) to give the crude title compound (2.40 g) as a light yellow solid. substance:

¹HNMR (DMSO-d 6, 300 MHz): δ ppm 3.28 (ZN, s), 3.61 (ZN, 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

174

54504 Β1

<img file="RS54504B1_D0118.tif" />

To 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) was added EtMgBr (1.0 M in THF, 7.04 mL, 7.04 mmol), at -78 ° C, under nitrogen. This mixture was stirred at -78 ° C for 1 h. The reaction was treated with saturated aqueous NH4Cl at -78 ° C. This mixture was warmed to room temperature, extracted with EtOAc, dried over IagZOd, 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:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 1.06 (ZN, 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).

Reference example 110

4-Bromo-3-phenyl-1H-pyrazole

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 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. This extract was digested 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 7.39-7.50 (ZN, m), 7.64 (1H, s), 7.77 (2H, d, J = 6.8 Hz), 10.73 (1H, brs).

Reference example 111

4-V-Z-phenyl-1-trityl-1H-pyrazole

175

54504 Β1

<img file="RS54504B1_D0119.tif" />

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 h at 90 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This extract was washed with water and brine, dried over MgSO 4 and 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;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), 7.87-7.91 (2H, m).

Anal. Calculation. for C₂₈H₂iBrN₂; 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

<img file="RS54504B1_D0120.tif" />

<img file="RS54504B1_D0121.tif" />

<img file="RS54504B1_D0122.tif" />

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 at 100 ° C for 2 h. To this mixture was added an 8 M solution of NaOH in water (22 mL), at 0 ° C. This mixture was stirred at room temperature for 2 h, diluted with brine, extracted with EtOAc, dried over Na₂SO4, filtered and concentrated in vacuo. The residue was taken up in EtOAc / i-Pr₂O and filtered. This filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100) and washed with EtOAc / hexane to give the title compound (2.50 g, 56% yield) as a light yellow solid. 1 H NMR (DMSO-d 6, 300 MHz): δ ppm 6.17 (1H, d, J = 7.5 Hz), 6.52 (2H, brs), 7.677.81 (2H, m), 8.04 (1H, d, J = 7.5 Hz), 8.10 (1H, s), 8.75 (1H, d, J = 7.5 Hz).

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Reference example 113

3-Bromo-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0123.tif" />

<img file="RS54504B1_D0124.tif" />

To DMF (18 mL) was added isoamyl nitrite (2.44 mL, 18.3 mmol) and SiVg (1.89 g, 8.46 mmol), at 0 ° C. To this mixture was added dropwise a solution of 3-amino-1- [3 (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (1.80 g, 7.05 mmol) in DMF (7.2 mL), then 0 ° C. This mixture was stirred at 0 ° C for 1 h and then at 60 ° C for 3 h. This mixture was diluted with brine, extracted with EtOAc, washed with brine, dried over MgSO 4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100), and triturated with hexane. to give the title compound (1.85 g, 82% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 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

<img file="RS54504B1_D0125.tif" />

-TMS

<img file="RS54504B1_D0126.tif" />

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) ), Cul (4.5 mg, 0.0236 mmol), Pd (PPh₃) 2CI₂ (55.1 mg, 0.0785 mmol) and RRz (10.3 mg, 0.0393 mmol) in THF (7.5 mL) were heated at 40 ° C for 8 h, under Ag. To this suspension was added (trimethylsilyl) acetylene (0.111 mL, 0.785 mmol). This suspension was heated at 40 ° C for 14 h, under Ar. To this suspension was added (trimethylsilyl) acetylene (0.0888 mL, 0.628 mmol). This suspension was heated at 40 ° C for 96 h, under Ag. This mixture was diluted with brine, extracted with EtOAc, dried over MdbOd, filtered, concentrated in vacuo and purified by column chromatography on silica gel.

177

54504 Β1 (hexane / EtOAc = 50/50 to 0/100), to give the title compound (148 mg, 28% yield) as a brown solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 0.26 (9H, s), 6.64 (1H, d, J = 7.9 Hz), 7.757.92 (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

<img file="RS54504B1_D0127.tif" />

<img file="RS54504B1_D0128.tif" />

<img file="RS54504B1_D0129.tif" />

A mixture of 1- [3- (trifluoromethyl) phenyl] -3 - [(trimethylsilyl) ethynyl] pyridazin-4 (1H) -one (148 mg, 0.439 mmol) in MeOH (3 mL) and a 1 M solution of NaOH in water ( 5 mL) was stirred at 0 ° C for 5 min and then at room temperature for 2 h. This mixture was neutralized with 1 M aqueous HCl at 0 ° C. This mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100) to give the title compound (69 mg, 59%). yield) as a light red solid:

¹1 H NMR (DMSOde, 300 MHz): δ ppm 4.70 (1H, s), 6.65 (1H, d, J = 7.9 Hz), 7.767.92 (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

<img file="RS54504B1_D0130.tif" />

To a solution of methyl 4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylate (2.00 g, 6.70 mmol) and THF (134 mL) was added DIBAL (1.5, 13.4 mL, 20.1 mmol), at -78 ° C. This solution was stirred at -78 ° C for 1 h, then slowly warmed to room temperature, stirred at room temperature for 18 h, diluted with 1 M aqueous HCl at 0 ° C, extracted with EtOAc, orege brine, dried over MgSCM. , filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc =

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50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30), giving the title compound (509 mg, 28% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 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), 8.08-8.16 (1H, m), 8.19 (1H, s), 8.94 (1H, d, J = 8.0 Hz).

Reference example 117

4-Oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carbaldehyde

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. To this suspension was added a solution of 3- (hydroxymethyl) 1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (509 mg, 1.88 mmol) in THF (7.5 mL), at -78 ° C. This suspension was stirred at -78 ° C for 1 h. To this mixture was added Et 3 N (1.05 mL, 7.52 mmol), then -78 ° C. This mixture was slowly warmed to room temperature, stirred at room temperature for 18 h, diluted with 1 M aqueous HCl, extracted with EtOAc, washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4, filtered, concentrated under by vacuum and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 70/30).

To a solution of oxalyl chloride (0.477 mL, 5.64 mmol) in THF (19 mL) was added DMSO (0.801 mL, 11.3 mmol) at -78 ° C. To this suspension was added a mixture of the above residue in THF (9.5 mL) at -78 ° C. This suspension was stirred at -78 ° C for 2 h. To this mixture was added EtaN (3.14 mL, 22.6 mmol) at -78 ° C. This mixture was slowly warmed to room temperature, stirred at room temperature for 17 h, diluted with 1 M HCl in water, extracted with EtOAc, washed with saturated aqueous IaNSO 2 and brine, dried over IagbSi, filtered, concentrated in vacuo and purify by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100) to give the title compound (257 mg, 51% yield) as a yellow solid:

¹1 H NMR (DMSO-d 6, 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).

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Reference example 118

5-Methoxy-4-oxo-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyridazine-3-carboxylic acid

<img file="RS54504B1_D0131.tif" />

Oh

1.

<img file="RS54504B1_D0132.tif" />

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 a 1 M solution of NaOH in water (61 mL), at 0 ° C. This mixture was stirred at room temperature for 30 min. To this solution was added a 1 M solution of HCl in water (61 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, washed with water and dried under vacuum at 60 ° C to give the title compound (8.78 g, 92% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.98 (ZN, s), 7.82-8.01 (2H, m), 8.11-8.34 (2H, m), 8.97 (1H, s), 15.00 (1H, brs) ).

Reference example 119

3-Amino-5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

<img file="RS54504B1_D0133.tif" />

<img file="RS54504B1_D0134.tif" />

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 Et 3 N (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated at 100 ° C for 2 h. To this mixture was added an 8 M solution of NaOH in water (23.8 mL), at 0 ° C. This mixture was stirred at room temperature for 3 h, extracted with EtOAc, dried over IagbOd, filtered and concentrated in vacuo. The residue was washed with EtOAc / i-RggO and filtered. This filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100) and recrystallized from EtOAc / hexane to give the title compound (3.57 g, 66% yield) as a light yellow solid. :

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.83 (ZN, s), 6.31 (2H, s), 7.64-7.79 (2H, m), 8.13 (2H, s), 8.64 (1H, s).

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54504 Β1

Reference Example 120 (2-Phenylfuran-3-yl) boric acid

To a mixture of 3-bromo-2-phenylfuran (6.70 g, 30.0 mmol) and V (OJ-Rg) z (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. This mixture was stirred at -78 ° C for 30 min and then at 0 ° C for 30 min. This 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:

¹1 H NMR (DMSO-d 6, δ): b ppm 6.64 (1H, d, J = 1.4 Hz), 7.21-7.45 (ZN, m), 7.69 (1H, d, J = 1.6 Hz), 8.00-8.08 2H, m).

Reference Example 121 (2-Phenylthiophen-3-yl) boric acid

<img file="RS54504B1_D0135.tif" />

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. This mixture was stirred at -78 ° C for 30 min and then at 0 ° C for 30 min. This mixture was diluted with 1 M HCl in water to 0 ° C, extracted with EtOAc, orege brine, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 90/10 to 0 / 100) to give the title compound (87.4 mg, 5% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 7.19 (1H, d, J = 4.9 Hz), 7.27-7.44 (ZN, m), 7.46-7.58 (ZN, m), 8.06 (2H, s).

Reference example 122

Methyl 4-methoxy-3-oxo-2- (pyridin-4-ylhydrazono) butanoate

181

54504 Β1

<img file="RS54504B1_D0136.tif" />

4-Aminopyridine (3.6 g, 38 mmol) was added to a mixture of phosphoric acid (10 mL, 150 mmol) and nitric acid (5 mL, 78 mmol) at -6 ° C. Sodium nitrite (3.2 g, 46 mmol) was added portionwise to this mixture, at -6 ° C, and then crushed ice (about 25 g) was added to the solution. After stirring at -6 ° C for 10 min, this 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. This mixture was partitioned between AcOEt and water. The aqueous layer was extracted with AcOEt. The combined organic extract was washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residual precipitate was digested with AcOEt / hexane (1/3) to give the title compound (1.8 g, 19% yield) as a yellow solid:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.48-3.53 (ZN, m), 3.89-3.95 (ZN, 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

A mixture of methyl 4-methoxy-3-oxo-2- (pyridin-4-ylhydrazono) butanoate (18 g, 70 mmol) and N, N-dimethylformamide dimethylacetal (28 mL, 210 mmol) in toluene (210 mL) was refluxed. 4 h. This mixture was concentrated under reduced pressure to give crystals. These crystals were washed with 2-propanol / AcOEt (1: 4) to give the title compound (8.2 g, 45% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.99 (ZN, s), 4.00 (ZN, 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

182

54504 Β1

<img file="RS54504B1_D0137.tif" />

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) was added 1 M solution of NaOH in water (3.0 mL, 3.0 mmol), and this mixture was stirred at room temperature overnight. This mixture was concentrated under reduced pressure. To the residue was added 1 M HCl solution in water (3.1 mL). The resulting precipitate was collected by filtration, dried with water and dried to give the title compound (0.47 g, 99% yield) as an off-white solid:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 3.98 (ZN, 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

<img file="RS54504B1_D0138.tif" />

<img file="RS54504B1_D0139.tif" />

To a mixture of 5-methoxyN-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) was added N, N-dimethylhydroxylamine hydrogen chloride (6.5 g, 66 mmol) and TEA (14 mL, 100 mmol), and the mixture was stirred at room temperature for several weekends. This mixture was concentrated under reduced pressure. The residue was diluted with water, saturated with K2CO3 and extracted with AcOEt. (It has three layers.) The highest, organic layer was dried over MgSO 3, filtered and concentrated under reduced pressure. The middle layer was extracted with CH 2 Cl 2 (50 mL x 4), and the combined extracts were dried over MgSO 4, 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 light yellow oil.

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.40 (ZN, s), 3.68 (ZN, s), 3.98 (ZN, 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

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54504 Β1

-Acetyl-5-methoxy-1-pyridin-4-ylpyridazin-4 (1H) -οα «•» -ΛΑ.

φ

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 over 15 min adds 1

M MeMgBr in THF (66 mL, 66 mmol), at -78 ° C. After stirring for 1 h at -78 ° C, this mixture was treated with a 1 M solution of HCl in water (70 mL). This mixture was warmed to room temperature, made basic with 1 M NaOH solution in water and washed with AcOEt. The aqueous layer was extracted with CH2Cl2 (50 mL χ 4). The combined extract was dried over MdbOd, filtered and concentrated under reduced pressure to give the title compound (2.1 g, 26% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.70 (ZN, s), 3.98 (ZN, 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

<img file="RS54504B1_D0140.tif" />

To a suspension of quinoline-8-amine (10.0 g, 69.4 mmol) in 6 M aqueous HCl (69.4 mL) was added a solution of NaNO 2 (5.74 g, 83.2 mmol) in water (13.9 mL), at 0 ° C. To a 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. This mixture was stirred at 0 ° C for 10 min. The precipitate was collected by filtration, dried with water and EtOAc and dried. To the solid residue was added N, N-dimethylformamide-dimethylacetal (255 mL), at room temperature. This mixture was heated at reflux for 2.5 h and then cooled to room temperature. The precipitate was collected by filtration, washed with hexane and dried to give the title compound (16.6 g, 77% yield) as a gray solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.77 (ZN, s), 3.80 (ZN, 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).

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Reference example 128

5-Methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylic acid

<img file="RS54504B1_D0141.tif" />

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 a 1 M solution of NaOH in water. 64 mL) and THF (64 mL), at 0 ° C. This mixture was heated to 80 ° C. The resulting homogeneous mixture was cooled to 0 ° C. To this mixture was added a 1 M solution of HCl in water (64 mL), at 0 ° C. This mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The precipitate was collected by filtration, germinated with water and dried under vacuum at 60 ° C to give the title compound (3.59 g, 75% yield) as a freshly colored substance:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.86 (ZN, 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-ylpyridazin-4 (1H) -one

<img file="RS54504B1_D0142.tif" />

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 at reflux for 1 h. To this suspension was added DMF (52 mL), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol), at room temperature. This mixture was heated at 100 ° C for 1.5 h. To this mixture was added an 8 M solution of NaOH in water (10.9 mL), at 0 ° C. This mixture was stirred at room temperature for 1.5 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100). 0 to 80/20) and on silica gel (EtOAc / MeOH = 100/0 to

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50/50), was triturated with EtOAc / hexane to give the title compound (479 mg, 20% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.75 (ZN, 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-ylpyridazin-4 (1H) -one

<img file="RS54504B1_D0143.tif" />

To DMF (3 mL) was added isoamyl nitrite (0.387 mL, 2.91 mmol) and SiVg (299 mg, 1.34 mmol), at 0 ° C. To this mixture was added a solution of 3-amino-5-methoxy-1-quinolin-8-ylpyridazin4 (1H) -one (300 mg, 1.12 mmol) in DMF (3 mL), at 0 ° C. This mixture was stirred at 0 ° C for 1 h and then at 60 ° C for 2.5 h. This mixture was diluted with water, extracted with EtOAc, orege brine, dried over MgSO 4, filtered, concentrated in vacuo, purified by column chromatography on 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 a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.78 (ZN, 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) boric acid

<img file="RS54504B1_D0144.tif" />

To a solution of 1-phenyl-1H-pyrazole (12.8 g, 88.9 mmol) in THF (355 mL) was added dropwise n-BuLi (1.6 3 M solution in hexane, 57.2 mL, 93.3 mmol), at -78 ° C, under nitrogen. This mixture was stirred at -78 ° C for 1 h. To this mixture was added B (Oi-Pr) 3 (82.0 mL, 355 mmol), at -78 ° C. The mixture was stirred at -78 ° C for 1 h, slowly warming to room temperature

186

54504 Β1 temperature and stir at room temperature overnight. The pH of this mixture was adjusted to 5 with 1 M aqueous HCl. This mixture was concentrated in vacuo, extracted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered, concentrated in vacuo and crystallized from MeOH / EtOAc / hexane to give the title compound (12.6 g, 76% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 6.73 (1H, brs), 7.28-7.39 (1H, m), 7.39-7.54 (4H, m), 7.66 (1H, s).

Reference example 132

1-Phenyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole

Έ to

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), at room temperature. This mixture was heated at 40 ° C for 2 days. This mixture was concentrated in vacuo and triturated with hexane to give the title compound (7.93 g, 64% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 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

<img file="RS54504B1_D0145.tif" />

<img file="RS54504B1_D0146.tif" />

<img file="RS54504B1_D0147.tif" />

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-benzodioxol-4-amine (3.0 g, 17 mmol) in 6 M solution. HCl in water (18 mL, 108 mmol), then 0 ° C. After stirring at 0 ° C for 15 min, this 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 to 0 ° C. . This mixture is

187

54504 Β1 distribution between AcOEt and water. The organic layer was stirred with brine, dried over MdbOd, filtered and concentrated under reduced pressure.

A solution of the residue in N, N-dimethylformamide dimethyl acetal (20 mL, 150 mmol) was refluxed for 3 h. This mixture was concentrated under reduced pressure. The residual precipitate was digested with AcOEt / hexane (1/3) to give the title compound (4.1 g, 71% yield) as an orange solid:

¹1 H NMR (300 MHz, CDCl 3)₃): b ppm 3.96 (ZN, s), 3.99 (ZN, 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 '-γ-ethyl

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) was added to a 1 M solution of NaOH in water (18 mL, 18 mmol), and the mixture was stirred at room temperature for 1 h. This mixture was concentrated under reduced pressure and acidified with 1 M aqueous HCl. This 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 substance:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 4.06 (ZN, 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

188

54504 Β1

To a mixture of 1- (2,2-difluoro-1,3-benzodioxol-4-yl) -5-methoxy-4-oxo-1,4-dihydropyridazine3-carboxylic acid (3.8 g, 12 mmol), HOBt (2.7 g) , 17 mmol) and WSC (3.4 g, 17 mmol) in DMF (50 [mu] L) were added N, N-dimethylhydroxylamine hydrogen chloride (2.3 g, 23 mmol) and E1zM (4.9 mL, 35 mmol), and this mixture was added stir at room temperature overnight. This mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL χ 2). The combined organic layer was stirred with saturated aqueous №NSO 2 solution and brine, dried over MgSO 4, filtered and concentrated under reduced pressure to give orange crystals. These crystals were washed with AcOEt / hexane (1/4) to give the title compound (2.7 g, 62% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.41 (ZN, s), 3.71 (ZN, s), 3.96 (ZN, 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-methoxypyridazin-4 (1H) -one

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, 1 Μ MeMgBr in THF (14 mL, 14 mmol), at -78 ° C, over 15 min. After stirring at -78 ° C for 1 h, this mixture was treated with 1 M aqueous HCl (30 mL). This mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound (2.3 g, 99% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.69 (ZN, s), 3.95 (ZN, 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

189

54504 Β1

<img file="RS54504B1_D0148.tif" />

NMS;

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 N, N-dimethylformamide dimethylacetal (75 mL) was refluxed for 3 h. This mixture was concentrated under reduced pressure. Vgaop crystals were washed with AcOEt / hexane (1/1) to give the title compound (2.0 g, 74% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.91 (ZN, s), 3.14 (ZN, s), 3.94 (ZN, 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

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 refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This 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 light yellow solid.

A solution of MagBgOd (34.8 g, 200 mmol) in H 2 O (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 this mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and extracted with AcOEt. This extract was digested with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic chromatography followed by silica gel column, eluting with hexane / AcOEt (1/1) to give the title compound (5.84 g, 42% yield) as a light brown oil:

190

54504 Β1 ¹1 NMR (300 MHz, CDCl 3): δ ppm 3.42 (2H, brs), 4.97 (2H, s), 6.60 (1H, ddd, J =

1.1, 2.6, 8.7 Hz), 6.67-6.74 (2H, m), 7.28-7.43 (5H, m).

Reference example 139

Methyl 2 - {[4- (benzyloxy) -2-fluorophenyl] hydrazono} -4-methoxy-3-oxobutanoate

<img file="RS54504B1_D0149.tif" />

A solution of NaNCl 2 (2.07 g, 30 mmol) in H 2 O (5 mL) was added dropwise over 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 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.24 mL, 24 mmol) and NaOAc (12.3 g, 150 mmol) in MeOH (50 mL), pre-cooled to 0 ° C. The reaction mixture was poured into water and extracted with AcOEt. This 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:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3,500 (ZN χ 0.46, s), 3,502 (ZN χ 0.54, s), 3.88 (ZN χ 0.54, s), 3.92 (ZN χ 0.46, s), 4.65 (2Η χ 0.46, s), 4.68 (2H χ 0.54, s), 5.06 (2Η χ 0.54, s), 5.07 (2N 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 x 0.54, t, J = 9.0 Hz), 13.12 (1H x 0.46, brs), 15.13 (1H χ 0.54, brs).

Reference example 140

Methyl 1- [4- (benzyloxy) -2-fluorophenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

191

54504 Β1

A solution of methyl 2 - {[4- (benzyloxy) -2-fluorophenyl] hydrazono} -4-methoxy-3-oxobutanoate (8.46 g, 22.6 mmol) in N, N-dimethylformamide dimethyl acetal (80 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. This residue was diluted with AcOEt, washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with THF and recrystallized from hexane / THF to give the title compound (8.12 g, 93% yield) as a white solid: mp. 143-144 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.89 (ZN, s), 3.96 (ZN, 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. Calculation. 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-1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0150.tif" />

To a solution of N, N-dimethylhydroxylamine hydrogen chloride (5.27 g, 54 mmol) and iPrzNEt (9.41 ml_.54 mmol) in CH2Cl2 (50 mL) was slowly added AI Mez (1.8 M solution in toluene, 30 mL, 54 mmol). ), at 0 ° C, in an Ar atmosphere. After stirring for 1 h, a solution of methyl 1- [4-benzyloxy-N-fluorophenyl-N-methoxy-oxo-N-dihydropyridazine-S-carboxylate (8.07 g, 21 mmol) in CH 2 Cl 2 (50 mL) was added slowly, and this mixture was added stirred for 1 h at 0 [deg.] C. The reaction mixture was poured into ice-water and extracted with AcOEt. This extract was digested with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic column chromatography on silica gel, eluting with AcOEt, to give the title compound (7.79 g, 90% yield) as a light yellow amorphous substance:

^P1 NMR (300 MHz, CDCl 3): δ ppm 3.38 (ZN, s), 3.70 (ZN, S), 3.89 (ZN, 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).

192

54504 Β1

Reference example 142

3-Acetyl-1- [4- (benzyloxy) -2-fluorophenyl] -5-methoxypyridazin-4 (1H) -one

<img file="RS54504B1_D0151.tif" />

MeMgBr (1 M solution in THF, 56.4 mL, 56.4 mmol) was added dropwise at -78 ° C to a solution of 1- [benzyloxy] -Z-fluorophenyl] -NS-dimethoxy-N-methyl-oxo-M-dihydropyridazine- 3-carboxamide (7.77 g, 18.8 mmol) in THF (120 mL). After stirring for 1 h, the reaction mixture was treated with 1 M aqueous HCl and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and crystallizing from hexane / AcOEt to give the title compound (5.86 g, 85% yield) as a light yellow solid: mp. 101-103 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.67 (ZN, s), 3.89 (ZN, s), 5.13 (2H, s), 6.84-6.93 (2H, m), 7.34-7.44 (5H, m), 7.48-7.55 (1 H, m), 7.69 (1 H, d, J = 2.3 Hz).

Anal. Calculation. 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

A mixture of 4-bromo-3-fluoro (trifluoromethoxy) benzene (6.6 g, 26 mmol), benzophenone imine (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 nitrogen for 5 h. After stirring at room temperature overnight, this mixture was concentrated under reduced pressure. This residue was partitioned between AcOEt and water. The organic layer was stirred with brine, dried over MgSO 3, filtered and concentrated under reduced pressure. This residue is chromatographed on

193

54504 Β1 silica gel (0 / 100-5 / 95 AcOEt / hexane), giving a yellow oil. This remaining oil was dissolved in THF (150 mL) and 1 M solution of HCl in water (50 mL) and added to this mixture. After stirring at room temperature for 1 h, this mixture was basified with 8 M aqueous NaOH and extracted with diethyl ether. The organic layer was stirred with brine, dried over MdbOd, filtered and concentrated under reduced pressure. This residue was chromatographed on silica gel (0 / 100-5 / 95 AcOEt / hexane) to give the title compound (4.2 g, 85% yield) as a pale yellow oil:

¹1 H NMR (300 MHz, DMSO-d 6): 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] hydrazono} -4-methoxy-3-oxobutanoate

<img file="RS54504B1_D0152.tif" />

A solution of sodium nitrite (1.9 g, 28 mmol) in NgO (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 at 0 ° C for 15 min, this 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 to 0 ° C. . The resulting precipitate was collected by filtration, dried with water and dried under reduced pressure to give the title compound (4.8 g, 58% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.51 (ZN, s), 3.94 (ZN, s), 4.65 (2H, s), 7.06-7.14 (2H, m), 7.59-7.68 (1H, m), 12.98 (1 H, brs).

Reference example 145

Methyl 1- [2-fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

<img file="RS54504B1_D0153.tif" />

<img file="RS54504B1_D0154.tif" />

194

54504 Β1

A solution of methyl 2 - {[2-fluoro-4- (trifluoromethoxy) phenyl] hydrazono} -4-methoxy-3-oxobutanoate (3.8 g, 11 mmol) and N, N-dimethylformamide-diisopropylacetal (9.5 mL, 54 mmol) in toluene ( 60 ml_) is refluxed for 5 h. This mixture was concentrated under reduced pressure. This residue was diluted with AcOEt, washed with water and brine. The organic layer was dried over MdbOd, filtered and concentrated under reduced pressure. This residue was chromatographed on silica gel (10 / 90-100 / 0 AcOEt / hexane) to give the title compound (3.4 g, 86% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.91 (ZN, s), 3.97 (ZN, s), 7.17-7.25 (2H, m), 7.68-7.76 (2H, m).

Reference example 146

1- [2-Fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazin-3-

<td>carboxylic acid</td><td>-CO _?H</td>

<td>In a solution of methyl</td><td>1- [2-fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-4-oxo-1,4-</td>

dihydropyridazine-3-carboxylate (3.4 g, 9.3 mmol) in THF (150 mL) was added to a 1 M solution of NaOH in water (14 mL, 14 mmol), and the mixture was stirred at room temperature for 30 min. This mixture was acidified with a 1 M solution of HCl in water and concentrated under reduced pressure. This 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 light yellow amorphous substance:

¹1 H NMR (300 MHz, DMSO-d 6): δ rrpp 3.88 (ZN, 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

<img file="RS54504B1_D0155.tif" />

<img file="RS54504B1_D0156.tif" />

CCF₃

195

54504 Β1

To 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) was added N, N-dimethylhydroxylamine hydrogen chloride (2.1 g, 22 mmol) and E1z1C (4.5 mL, 32 mmol), and the mixture was stirred at room temperature over nights. This mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL χ 2). The combined organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 4.₄, filtered and concentrated under reduced pressure.

To a solution of this residue in THF (100 mL) was added dropwise, 1 M MeMgBr in THF (18 mL, 18 mmol), at -78 ° C, over 15 min. After stirring at -78 ° C for 1 h, this mixture was treated with 1 M aqueous HCl (50 mL). This mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO 4._4| filtered and concentrated under reduced pressure to give the title compound (2.8 g, 75% yield) as a yellow oil:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.68 (ZN, s), 3.91 (ZN, 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

<img file="RS54504B1_D0157.tif" />

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. This mixture was stirred at room temperature for 12 h and then concentrated in vacuo. This residue was diluted with 6 M aqueous HCl (62 mL). NaNO solution was added to this suspension₂ (2.06 g, 29.9 mmol) in water (5 mL), at 0 ° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (3.22 mL, 24.9 mmol) and NaOAc (92.9 g) in EtOH (84 mL) was added the above mixture, at 0 ° C. This mixture was stirred at 0 ° C for 20 min. The precipitate was collected by filtration, diluted with EtOAc, washed with a solution of NaHCO 3 in water, dried over MdbOd, filtered and concentrated in vacuo to give the title compound (5.36 g, 62% yield) as a brown solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.30 (ZN, s), 3.75-3.94 (ZN, 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).

196

54504 Β1

Reference example 149

Methyl 1- (3-bromo-2-fluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

A mixture of methyl 2 - [(3-bromo-2-fluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate (5.36 g, 15.4 mmol) in N, N-dimethylformamide dimethylacetal (54 mL) was heated at reflux for 2 h, and cooled to 0 ° C. The precipitate was collected by filtration, the walnuts with hexane and dried to give the title compound (4.16 g, 75% yield) as a brown solid:¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.80 (ZN, s), 3.83 (ZN, 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

ΌΗ

To 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) was added a 1 M solution of NaOH in water (23 mL), at 0 ° C. This mixture was stirred at room temperature for 1 h. To this solution was added a 1 M solution of HCl in water (23 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, dried with water and dried under vacuum at 50 ° C to give the title compound (3.76 g, 94% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6)₆, 300 MHz): b ppm 3.87 (ZN, s), 7.43 (1H, td, J = 8.1, 1.5 Hz), 7.76-7.85 (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

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54504 Β1

1- (3-Bromo-2-fluorophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide ο ο

IMEO, D Jt -OMa

<img file="RS54504B1_D0158.tif" />

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 at 40 ° C for 2 h. To this solution were added N, N-dimethylhydroxylamine hydrogen chloride (1.60 g, 16.4 mmol) and i-Pr2NEt (2.86 mL, 16.4 mmol), at room temperature. This mixture was stirred at room temperature for 18 h. This mixture was diluted with water and 1 M HCl in water, extracted with EtOAc, dried over IagbOd, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (EtOAc / MeOH - 100/0 to 80/20) to give the title compound (4.22 g,&gt; 99% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.25 (ZN, s), 3.58 (ZN, s), 3.80 (ZN, s), 7.39 (1H, td, J = 8.1, 1.5 Hz), 7.78 1 H, 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

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 nitrogen. This mixture was stirred at -78 ° C for 2 h. The reaction was treated with a saturated solution of NH4Cl in water at -78 ° C. This mixture was diluted with a solution of NaHCO 3 in water, extracted with EtOAc, dried over IagbOd, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc / MeOH = 100/0 to 50/50) to give the title compound (3.48 g, 93% yield) as a yellow solid:

198

54504 Β1 ¹1 H-NMR (DMSO-d 6, 300 MHz): δ ppm 2.50 (ZN, s), 3.80 (ZN, 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) hydrazono] butanoate

MeO, | G ΟΜε

..... N

<img file="RS54504B1_D0159.tif" />

To a suspension of 2,2,6-trifluoro-1,3-benzodioxol-5-amine (4.95 g, 25.9 mmol) in 6 M aqueous HCl (25.9 mL) was added a solution of NaNCh (2.15 g, 31.1 mmol) in water. (5.2 mL), at 0 ° C. To a 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. This mixture was stirred at 0 ° C for 10 min. The precipitate was collected by filtration, washed with water, dissolved in EtOAc, orege brine and aqueous IaNSO 2, dried over MdbOd, filtered and concentrated in vacuo to give the title compound (6.31 g, 70% yield) as a red solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.33 (ZN, s), 3.82 (ZN, s), 4.66 (2H, s), 7.577.92 (2H, m), 12.32 (1H, brs).

Reference example 154

Methyl 5-methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine-3-carboxylate

<img file="RS54504B1_D0160.tif" />

Mixture of methyl 4-methoxy-3-oxo-2 - [(2,2,6-trifluoro-1,3-benzodioxol-5-yl) hydrazono] butanoate (6.31 g, 18.1 mmol) in N, N-dimethylformamide dimethylacetal (63 mL) was heated at reflux for 2.5 h. This mixture was concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 5 0/50 to 0/100 and EtOAc / MeOH - 100/0 to 70/30) and on basic silica gel (hexane / EtOAc = 50 / 50 to

199

54504 Β1

0/100), to give the title compound (1.53 g, 24% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, δ): b ppm 3.79 (ZN, s), 3.82 (ZN, s), 7.94 (1H, d, J = 9.4 Hz), 8.04 (1H, d, J = 6.4 Hz) , 8.54 (1 H, s).

Reference example 155

5-Methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine-3-carboxylic acid

<img file="RS54504B1_D0161.tif" />

To 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) was added to a 1 M solution of NaOH in water (8.5 mL), at 0 ° C. This mixture was stirred at room temperature for 30 min. To this mixture was added a 1 M solution of HCl in water (8.5 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, washed with water and dried under vacuum at 60 [deg.] C. to give the title compound (1.18 g, 80% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, δ): 6 ppm 3.86 (ZN, s), 7.98 (1H, d, J = 9.4 Hz), 8.03 (1H, d, J = 6.4 Hz), 8.79 (1H, s) , 14.77 (1 H, brs).

Reference example 156

3-Amino-5-methoxy-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0162.tif" />

5-Methoxy-4-oxo-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) -1,4-dihydropyridazine3-carboxylic acid mixture (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and EtaN (0.715 mL, 5.13 mmol) in toluene (12 mL) were heated at 100 ° C for 1 h. To this mixture was added 8 M solution of NaOH in water (4.3 mL), at 0 ° C. This mixture was stirred at room temperature

200

54504 Β1 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100), then recrystallized from EtOAc / hexane to give the title compound. mg, 65% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.73 (ZN, s), 6.21 (2H, s), 7.85 (1H, d, J = 9.4 Hz), 7.90 (1H, d, J = 6.4 Hz) , 8.33 (1 H, s).

Reference example 157

3-Bromo-5-methoxy-1- (2,2,6-trifluoro-1,3-benzodioxol-5-yl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0163.tif" />

To a mixture of isoamyl nitrite (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. This mixture was stirred at 0 ° C for 1 h and then at 60 ° C for 2 h. This mixture was diluted with water and brine, extracted with EtOAc, dried over NazSOc, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100) to give the title compound (145 mg, 60% yield) as a light yellow solid: ¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.79 (ZN, 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-6yl) hydrazono] butanoate

<img file="RS54504B1_D0164.tif" />

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 a 6 M solution of HCl in water (20.2 mL) was added a solution of NaNCh (1.67 g,

24.2 mmol) in water (4 mL), at 0 ° C. This mixture was stirred at 0 ° C for 15 min. In suspension

201

54504 Β1 methyl 4-methoxy-3-oxobutanoate (2.61 mL, 20.2 mmol) and NaOAc (30.3 g) in EtOH (34 mL) was added to the above solution, at 0 ° C. This mixture was stirred at 0 ° C for 15 min. The precipitate was 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:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.33 (ZN, s), 3.82 (ZN, s), 4.68 (2H, s), 7.667.93 (2H, m), 12.16 (1H, 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

A mixture of methyl

<img file="RS54504B1_D0165.tif" />

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-dimethylformamidimethylacetal (68 mL) was heated at reflux for 2.5 h. This mixture was concentrated in vacuo, diluted with brine, extracted with EtOAc, dried over MgSO 4, filtered, concentrated in vacuo, and purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100 / 0 to 70/30) and on basic silica gel (hexane / EtOAc = 80/20 to 0/100 and EtOAc / MeOH = 100/0 to 70/30), giving the title compound (2.58 g, 37% yield) as a light yellow solid substance:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.79 (ZN, s), 3.83 (ZN, 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

202

54504 Β1

<img file="RS54504B1_D0166.tif" />

To a solution of 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 (2.58 g, 6.31 mmol) in MeOH (26 mL) was added to a 1 M solution of NaOH in water (13 mL), at 0 ° C. This mixture was stirred at room temperature for 90 min. To this mixture was added a 1 M solution of HCl in water (13 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, washed with water and dried under vacuum at 60 ° C to give the title compound (2.33 g, 94% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.86 (ZN, s), 8.06 (1H, d, J = 10.2 Hz), 8.17 (1H, d, J = 6.8 Hz), 8.82 (1H, s) , 14.66 (1 H, brs).

Reference example 161

3-Amino-5-methoxy-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) pyridazin-4 (1H) -one

<img file="RS54504B1_D0167.tif" />

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-carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 mL, 8.86 mmol) and EIzM (1.23 mL, 8.86 mmol) in toluene (23 mL) were heated at 100 ° C for 90 min. To this mixture was added an 8 M solution of NaOH in water (7.4 mL), at 0 ° C. This mixture was stirred at room temperature for 2 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100) and then silica gel ( hexane / EtOAc = 80/20 to 0/100), then triturated with EtOAc / hexane to give the title compound (1.12 g, 53% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.73 (ZN, 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).

203

54504 Β1

Reference example 162

3-Bromo-5-methoxy-1- (2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) pyridazin-4 (1N) -op

<img file="RS54504B1_D0168.tif" />

<img file="RS54504B1_D0169.tif" />

To a mixture of isoamyl nitrite (0.473 mL, 3.56 mmol) and SiVgg (367 mg, 1.64 mmol) in DMF (5 mL) was added a mixture of 3-amino-5-methoxy-1- (2,2,3,3,7- 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. This mixture was stirred at 0 ° C for 1 h and at 60 ° C for 2.5 h. This mixture was diluted with water and brine, extracted with EtOAc, dried over MgSO 4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane / EtOAc = 50/50 to 0/100) and crystallized with EtOH / hexane to give the title compound (381 mg, 65% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 3.79 (ZN, s), 8.02 (1H, d, J = 10.5 Hz), 8.14 (1H, d, J = 6.8 Hz), 8.63 (1H, s) .

Reference example 163

- [2-Fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0170.tif" />

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), IagSO 2 (302 mg, 2.85 mmol) and Pd (PPh 3) 4 (74.5 mg, 0.0645 mmol) in DME (11.4 mL) and water (2.9 mL) was heated at reflux for 15 h, under Ar. This mixture was diluted with water, extracted with EtOAc, washed with brine, dried over IagbOd, filtered, concentrated in vacuo and purified

204

54504 Β1 column chromatography with basic silica gel (EtOAc / MeOH = 100/0 to 70/30) to give the title compound (345 mg, 69% yield) as a white solid:

¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 3.25 (ZN, s), 3.59 (ZN, s), 3.80 (ZN, s), 3.90 (ZN, 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).

Reference example 164

3-Acetyl-1- [2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazin-4 (1H) -one

<img file="RS54504B1_D0171.tif" />

To 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 nitrogen. This mixture was stirred at -78 ° C for 100 min. The reaction was treated with saturated aqueous NFkCl at -78 ° C. This mixture was extracted with EtOAc, dried over IagZOd, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc / MeOH = 100/0 to 70/30) to give the title compound (243 mg, 80% yield) as a white solid substance:

¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 2.51 (ZN, brs), 3.81 (ZN, s), 3.91 (ZN, s), 7.387.46 (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

<img file="RS54504B1_D0172.tif" />

To a suspension of 2-fluoro-5-iodoaniline (9.83 g, 41.5 mmol) in 6 M aqueous HCl (83.0 mL) was added a solution of NaNCl 3 (3.43 g, 49.8 mmol) in water (8.3 mL), at 0 ° C. U

205

54504 To a 1 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. This mixture was stirred at 0 ° C for 10 min. The precipitate was collected by filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO 4.₄, filtered and concentrated in vacuo to give the title compound (14.2 g, 87% yield) as a red solid:

¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 3.31 (ZN, s), 3.83 (ZN, s), 4.64 (2H, s), 7.037.41 (1H, m), 7.43-7.66 (1H, m) , 7.85-8.07 (1 H, m), 12.20 (1 H, brs).

Reference example 166

Methyl 1- (2-fluoro-5-iodophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

<img file="RS54504B1_D0173.tif" />

A mixture of methyl 2 - [(2-fluoro-5-iodophenyl) hydrazono] -4-methoxy-3-oxobutanoate (14.2 g, 35.9 mmol) in N, N-dimethylformamide dimethyl acetal (142 mL) was heated at reflux for 1.5 h and cooled. at 0 ° C. The precipitate was collected by filtration, washed with hexane and dried to give the title compound (11.3 g, 78% yield) as a light yellow solid:³1 H NMR (DMSO-d 6, 300MHz): δ ppm 3.80 (ZN, s), 3.82 (ZN, 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

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) was added a 1 M solution of NaOH in water (56 mL), at 0 ° C. This mixture was stirred at room temperature for 90 min. To this mixture was added a 1 M solution of HCl in water (56 mL), at 0 ° C. This mixture was concentrated in vacuo. The precipitate was collected by filtration, washed with water and dried under vacuum at 60 ° C to give the title compound (9.96 g, 91% yield) as a yellow solid:

206

54504 Β1 ¹Η NMR (DMSO-d 6, 300MHz): δ ppm 3.88 (ZN, 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, brs).

Reference Example 168 1- (2-Fluoro-5-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0174.tif" />

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 at 40 ° C for 30 min and then at 50 ° C for 90 min. DMF (20 mL) was added to this mixture. This mixture was stirred at 50 ° C for 70 min. To this solution were added N, O-dimethylhydroxylamine hydrogen chloride (3.74 g, 38.3 mmol) and i-Pr2NEt (6.67 mL, 38.3 mmol), at room temperature. This solution was stirred at room temperature for 16 h. This mixture was concentrated in vacuo, diluted with water and 1 M HCl in water, extracted with EtOAc, walnuts with saturated aqueous NaHCO 3 solution, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane / Ethanol / Et. 20/80 to 0/100 and EtOAc / MeOH - 100/0 to 0/100), then triturated with MeOH / EtOH / hexane to give the title compound (9.11 g, 82% yield) as a light yellow solid:

¹1 H NMR (DMSO-d 6, 300MHz, δ ppm 3.24 (ZN, s), 3.56 (ZN, s), 3.80 (ZN, 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).

Reference example 169

1- [2-Fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-rhetyl-4-oxo-1,4-dihydropindazine-3-carboxamide

207

54504 Β1

<img file="RS54504B1_D0175.tif" />

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), MagSO 2 (268 mg, 2.53 mmol) and Pd (PPh3&gt; 4 (66.4 mg, 0.0575) mmol) in DME (10.1 mL) and water (2.5 mL) was heated at reflux for 14 h, under Ar. This mixture was diluted with water, brine and saturated aqueous MaNSO 2, extracted with EtOAc, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane / EtOAc = 50/50 to 0/100 and EtOAc / MeOH = 100/0 to 60/40), giving the title compound (267 mg, 60% yield) as a light yellow solid: ¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 3.25 (ZN, s), 3.59 (ZN, s), 3.82 (ZN, s), 3.87 (ZN, 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 (1H, s).

Reference example 170

3-Acetyl-1- [2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazin-4 (1H) -one

<img file="RS54504B1_D0176.tif" />

<img file="RS54504B1_D0177.tif" />

In a mixture of 1- [2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-

1,4-Dihydropyridazine-3-carboxamide (267 mg, 0.687 mmol) in THF (80 mL) was added MeMgBr (1.0 M in THF, 2.06 mL, 2.06 mmol), at -78 ° C, under nitrogen. This mixture was stirred at -78 ° C for 2 h. To this mixture was added MeMgBr (1.0 M in THF, 0.687 mL, 0.687 mmol), at -78 ° C. This mixture was stirred at -78 ° C for 1 h. To this mixture was added MeMgBr (1.0 M in THF, 1.37 mL, 1.37 mmol), at -78 ° C. This mixture was stirred at -78 ° C for 3 h. The reaction was treated with saturated aqueous NFUCI solution at -78 ° C. This mixture was diluted with saturated aqueous NaHCO 3, extracted with EtOAc, dried over Na 2 SO 4, filtered, concentrated in vacuo and purified by column chromatography with

208

54504 Β1 silica gel (EtOAc / MeOH = 100/0 to 70/30), giving the title compound (201 mg, 85% yield) as a yellow solid:

¹1 H NMR (DMSO-d 6, 300MHz): δ ppm 2.52 (ZN, s), 3.82 (ZN, s), 3.87 (ZN, 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

Suspension 1 H-pyrazole-4-boronic acid pinacol ester (5.16 g, 26.6 mmol), CF₂CICO₂Na (4.86 g, 31.9 mmol) and 18-crown-6 (1.41 g, 5.32 mmol) in CHsCN (100 mL) were refluxed for 20 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This extract was digested with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic column chromatography on silica gel, eluting with AcOEt, to give the title compound (3.03 g, 47% yield) as a yellow oil:

¹1 H NMR (300 MHz, CDCl 3): 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

<img file="RS54504B1_D0178.tif" />

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin4 (1H) -one suspension (2.44 g, 5.0 mmol), tert-butyl carbazate (0.727 g, 5.5 mmol), Cul (0.0095 g, 0.05 mmol), 1,10-phenanthroline (0.072 g, 0.4 mmol) and Sz₂The SO 2 (2.28 g, 7.0 mmol) in DMF (25 mL) was stirred at 100 ° C for 5 h under Ar. After cooling to room temperature

209

54504 Β1 temperature, the reaction mixture was poured into water and extracted three times with AcOEt. The combined extracts were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and crystallizing from hexane / AcOE to give the title compound (2.04 g, 83% yield) as a light yellow solid: mp. 163-165 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 1.58 (9H, s), 3.90 (ZN, 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. Calculation. 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] hydrazono} pentane-2,4-dione

<img file="RS54504B1_D0179.tif" />

2- (1-Methylethyl) aniline (2.00 g, 14.81 mmol) was added to a solution of 12 mL of phosphoric acid (85%) and 8 mL of nitric acid (65%), at -6 ° C, then sodium nitrite ( 1.23 g, 17.78 mmol) in 4 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A solution of potassium acetate (4.35 g, 44.43 mmol) and acetylacetone (1.92 g, 19.25 mmol) in 80 mL of ethanol and 20 mL of water was then added dropwise to the mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / hbO (1/1) and hexane and dried to give the title compound (0.98 g, 27% yield):

Ή NMR (400 MHz, CDCl 3): δ ppm 1.34 (6H, d, J = 6.8 Hz), 2.52 (ZN, s), 2.63 (ZN, s), 3.12-3.21 (1H, m), 7.19-7.23 ( 1 H, 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

210

54504 Β1

<img file="RS54504B1_D0180.tif" />

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, then sodium nitrite was added dropwise (3.50 g, 50.78 mmol) in 10 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A solution of potassium acetate (12.45 g, 127.11 mmol) and acetylacetone (5.51 g, 55.08 mmol) in 80 mL of ethanol and 48 mL of water was then added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / hEO (1/1) and hexane and dried to give the title compound (4.00 g, 41% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (ZN, s), 2.63 (ZN, 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-ylhydrazono) pentane-2,4-dione

<img file="RS54504B1_D0181.tif" />

<img file="RS54504B1_D0182.tif" />

Biphenyl-2-amine (500 mg, 2.96 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C, and then sodium nitrite ( 254 mg, 3.55 mmol) in 1 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A solution of potassium acetate (870 mg, 8.88 mmol) and acetylacetone (385 mg, 3.85 mmol) in 60 mL of ethanol and 32 mL of water was then added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / hhO (1/1) and hexane, and dried to give the title compound (420 mg, 51% yield): ¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (ZN, s), 2.52 (ZN, s), 7.29-7.60 (9H, m), 14.63 (1H, s).

Reference example 176

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

211

54504 Β1

<img file="RS54504B1_D0183.tif" />

2-Ethoxyaniline (2.00 g, 14.60 mmol) was added to a solution of 12 mL of phosphoric acid (85%) and 8 mL of nitric acid (65%) at -6 ° C, then sodium nitrite (1.21 g) was added dropwise. , 17.52 mmol) in 10 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A solution of potassium acetate (4.29 g, 43.80 mmol) and acetylacetone (1.90 g, 18.98 mmol) in 60 mL of ethanol and 25 mL of water was then added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / HzO (1/1) and hexane and dried to give the title compound (2.00 g, 55% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 1.57 (ZN, t, J = 7.2 Hz), 2.53 (ZN, s), 2.63 (ZN, 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 (1H, s).

Reference example 177

3 - {[2-1-Methylethoxy) phenyl] hydrazono} pentane-2,4-dione

<img file="RS54504B1_D0184.tif" />

Add 2- (1-methylethoxy) aniline (1.00 g, 6.62 mmol) to a solution of 6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%) at -6 ° C, then add sodium nitrite ( 0.55 g, 7.95 mmol) in 2 mL of water, at 0 ° C, and this mixture was stirred for 30 min at 0 ° C. A solution of potassium acetate (1.95 g, 19.86 mmol) and acetylacetone (0.86 g, 8.61 mmol) in 40 mL of ethanol and 10 mL of water was then added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / hkO (1/1) and hexane and dried to give the title compound (0.53 g, 30% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 1.28-1.41 (6H, m), 2.50 (ZN, s), 2.63 (ZN, 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

212

54504 Β1

<img file="RS54504B1_D0185.tif" />

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

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, then sodium nitrite was added dropwise. (389 mg, 5.64 mmol, 1.0 equiv.) In 2 mL of water, at 0 ° C, and the mixture was stirred at 0 ° C for 30 min. A mixture of potassium acetate (1.66 g, 16.92 mmol) and acetylacetone (564 mg, 5.64 mmol) in 80 mL of ethanol and 48 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, ΕϊΟΗ / ΗςΟ (1/1) and hexane and dried to give the title compound (1.3 g, 80% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.54 (s, ZN), 2.65 (s, ZN), 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) hydrazono] pentane-2,4-dione

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, then sodium nitrite was added dropwise (0.90 g). , 12.97 mmol) in 2 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A mixture of potassium acetate (3.18 g, 32.43 mmol) and acetylacetone (1.40 g, 14.05 mmol) in 80 mL of ethanol and 48 mL of water was then added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / FhO (1/1) and hexane and dried to give the title compound (1.00 g, 31% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (ZN, s), 2.63 (ZN, s), 7.26-7.88 (9H, m), 14.91 (1H, s).

Reference example 180

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

213

54504 Β1

<img file="RS54504B1_D0186.tif" />

Add 2- (methylsulfinyl) aniline (0.50 g, 3.22 mmol) to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%, at -6 ° C), then sodium nitrite is added dropwise (0.27 g , 3.87 mmol) in 2 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. Then a mixture of potassium acetate (0.95 g, 9.66 mmol) and acetylacetone (0.42 g, 4.19 mmol) in 80 mL of ethanol and 48 mL of water was added dropwise to this reaction mixture. This mixture was stirred at room temperature overnight, filtered, washed with water, EtOH / bbO (1/1) and hexane and dried to give the title compound (0.66 g, 77% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.07 (ZN, s), 2.55 (ZN, s), 2.64 (ZN, s), 7.29-7.87 (4H, m), 15.06 (1H, s).

Reference example 181

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

3- (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, then sodium nitrite was added dropwise. (389 mg, 5.64 mmol) in 2 mL of water at 0 ° C, and this mixture was stirred at 0 ° C for 30 min. A mixture of potassium acetate (1.66 g, 16.92 mmol) and acetylacetone (564 mg, 5.64 mmol) in 80 mL of ethanol and 48 mL of water was then added dropwise to the reaction mixture. This mixture was stirred at room temperature overnight, filtered, dried with water, EtOH / hhO (1/1) and hexane, and dried to give the title compound (1.2 g, 74% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.49 (s, ZN), 2.61 (s, ZN), 7.05-7.08 (m, 1H), 7.25-7.27 (m, 1H), 7.32 (s, 1H), 7.42 (t, J = 8.0 Hz, 1 H), 14.59 (s, 1 H).

Reference example 182

N- {4- [2- (1-Acetyl-2-oxopropyridine)

214

54504 Β1

-V

<img file="RS54504B1_D0187.tif" />

<img file="RS54504B1_D0188.tif" />

N '(4-aminophenyl) acetamide (1000 mg, 6.66 mmol) was added to a solution of 6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and solid sodium nitrite (460 mg, 6.66 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of a saturated solution of №gSO 2 in water, extracted with dichloromethane, washed with water and brine, dried over MagbSM and concentrated under reduced pressure to give the title compound (1400 mg, 80% yield). :

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.22 (ZN, s), 2.48 (ZN, s), 2.60 (ZN, 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

<img file="RS54504B1_D0189.tif" />

<img file="RS54504B1_D0190.tif" />

N, N-Dimethylbenzene-1,4-diamine (500 mg, 3.67 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and sodium nitrite (253 mg, 3.67 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of a saturated solution of №gSO 2 in water, extracted with dichloromethane, washed with water and brine, dried over NazSCU and concentrated under reduced pressure to give the title compound (870 mg, 96% yield). as a brown solid:

215

54504 Β1 ¹Η NMR (400 MHz, CDCl 3): δ ppm 2.89 (ZN, s), 2.93 (ZN, s), 2.96 (ZN, s), 3.16 (ZN, s), 7.77-7.83 (4H, m), 14.80 1H, brs).

Reference example 184

3 - {[4- (4-Methylpiperazin-1-yl) phenyl] hydrazono} pentane-2,4-dione

4- (4-Methylpiperazin-1-yl) aniline (1000 mg, 5.24 mmol) was added to a solution of 6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and sodium nitrite (361 mg, 5.24 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min and then added to 250 mL of saturated Na solution₂CO3 in water, extracted with dichloromethane, orega water and brine, dried over Na₂SO4 and concentrated under reduced pressure to give the title compound (610 mg, 39% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.40 (ZN, s), 2.50 (ZN, s), 2.62 (ZN, 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 (1H, brs).

Reference Example 185 3 - {[4- (1H-1,2,4-Triazol-1-yl) phenyl] hydrazono} pentane-2,4-dione

<img file="RS54504B1_D0191.tif" />

4- (1H-1,2,4-Triazol-1-yl) aniline (500 mg, 3.12 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When this mixture reached room temperature, it was cooled to -6 ° C and sodium nitrite was added over 10 minutes.

216

54504 Β1 (216 mg, 3.12 mmol). Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min and then added to 250 mL of a saturated solution of IagSO 2 in water, extracted with dichloromethane, washed with water and brine, dried over NasCl 3 and concentrated under reduced pressure to give the title compound (600 mg, 71% yield) as brown solid:

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.54 (ZN, s), 2.63 (ZN, 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

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, then sodium nitrite was added dropwise (0.601). g, 8.7 mmol, 1.2 equiv.) in 10 mL of water, at 0 ° C, and the mixture was stirred for 30 min at 0 ° C. A mixture of potassium acetate (2.028 g, 20.7 mmol, 3.0 equiv.) And acetylacetone (0.8 mL, 7.0 mmol, 1.0 equiv.) In 20 mL of ethanol was then added dropwise to the reaction mixture. This mixture was stirred at room temperature for 15 min, filtered, 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.

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (s, ZN), 2.61 (s, ZN), 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] hydrazono} pentane-2,4-dione

217

54504 Β1

To a solution of 2-fluoro-3- (trifluoromethyl) aniline (1.0 g, 5.58 mmol) in 8 mL of acetic acid and

1.3 mL of concentrated hydrogen chloride solution, sodium nitrite (462 mg, 6.69 mmol) in 2.1 mL of water was added dropwise at 0 ° C, and this mixture was stirred for 1 h at 0 ° C. Sodium acetate (1.37 g, 16.8 mmol) and acetylacetone (726 mg, 7.26 mmol) were then added to the reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH / H 2 O (1/1) and hexane, and dried to give the title compound (900 mg, 55% yield).

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.63 (s, ZN), 7.30-7.34 (m, 1H), 7.38-7.41 (m, 1H), 7.94-7.96 (m, 1H) ), 14.66 (s, 1 H).

Reference example 188

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

To a solution of 2,3-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrogen chloride solution, sodium nitrite was added dropwise (600 mg,

9.3 mmol) in 2.7 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. A mixture of sodium acetate (1.78 g, 21.7 mmol, 3.0 equiv.) And acetylacetone (1 g, 10 mmol, 1.3 equiv.) Was then added dropwise to the reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH / hbO (1/1) and hexane and dried to give the title compound (900 mg, 48% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.49 (s, ZN), 2.61 (s, ZN), 6.93-7.00 (m, 1H), 7.11-7.17 (m, 1H), 7.50-7.56 (m, 1H) ), 14.64 (s, 1 H).

Reference Example 189 3 - [(2,2-Difluoro-1,3-benzodioxol-4-yl) hydrazono] pentane-2,4-dione

To a solution of sodium nitrite (0.96 g, 14 mmol) in NgO (5 mL) was added dropwise a solution of 2,2-difluoro-1,3-benzodioxol-4-amine (2.0 g, 12 mmol) in 6 M solution. HCI u

218

54504 Β1 water (12 mL, 72 mmol), at 0 ° C. After stirring at 0 ° C for 15 min, this 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 to 0 °. C. The resulting precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was dried with saturated aqueous MaNSO 2 and brine, dried over MgSO 3, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 90% yield) as orange crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.49 (ZN, s), 2.63 (ZN, 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] hydrazono} pentane-2,4-dione

To a solution of 2-fluoro-4- (trifluoromethyl) aniline (1.0 g, 5.58 mmol) in 8 mL of acetic acid and

1.3 mL of concentrated hydrogen chloride solution, sodium nitrite (462 mg, 6.69 mmol) in 2.1 mL of water was added dropwise at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. Sodium acetate (1.37 g, 16.8 mmol, 3.0 equiv.) And acetylacetone (726 mg, 7.26 mmol, 1.3 equiv.) Were then added to this reaction mixture. The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH / HEO (1/1) and hexane and dried to give the title compound (720 mg, yield 44%);

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.63 (s, ZN), 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

NHBoc

OCHF.

219

54504 Β1

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 h and then concentrated . The residue was dissolved in dichloromethane (40 mL), washed with 1 M aqueous HCl, dried over IagbOd and concentrated under reduced pressure. This crude product was purified by flash chromatography on silica gel (petroleum ether / AcOEt = 4/1) to give the title compound (850 mg, 63% yield) as a yellow solid:

¹1 H NMR (400 MHz, CDCl 3): 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, 1 H).

Reference example 192

3 - {[4- (Difluoromethoxy) -2-fluorophenyl] hydrazono} pentane-2,4-dione

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.

To a solution of this residue in 5.5 mL of acetic acid and 0.9 mL of concentrated hydrogen chloride solution, sodium nitrite (239 mg, 3.39 mmol) in 1.4 mL of water was added dropwise at 0 ° C, and this mixture was stirred for 1 h at 0 ° C. Sodium acetate (703 mg, 8.47 mmol, 3.0 equiv.) And acetylacetone (367 mg, 3.67 mmol, 1.3 equiv.) Were then added to this reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, dried with water, EtOH / hhO (1/1) and hexane, and dried to give the title compound (300 mg, 37% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.49 (s, ZN), 2.62 (s, ZN), 6.51 (t, J = 72.8 Hz, 1H), 6.95-7.04 (m, 2H), 7.73-7.77 ( m, 1 H), 14.70 (s, 1 H).

Reference example 193

2-Fluoro-4- (trifluoromethoxy) benzoic acid

220

54504 Β1

A solution of 1-bromo-2-fluoro-4- (trifluoromethoxy) benzene (8 g, 30.8 mmol) in 170 mL of THF was cooled to -40 ° C and then injected with i-PrMgBr (0.4 mol / L in THF, 91 mL). After stirring for 3 h, CO2 was introduced for 2 h at 0 ° C. This mixture was stirred with 1M HCl solution in water 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 stirred with petroleum ether to give 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 Ηζ, 1H).

Reference Example 194 tert-Butyl [2-fluoro4- (trifluoromethoxy) phenyl] carbamate

A solution of 2-fluoro-4- (trifluoromethoxy) benzoic acid (3 g, 13.4 mmol), DPPA (4.4 g, 16.1 mmol) and EIz (1.63 g, 16.1 mmol) in 130 mL of t-BuOH was refluxed for 4 h and then concentrates. This residue was dissolved in dichloromethane (200 mL), washed with 1M aqueous HCl, dried over Na2SO4 and concentrated under reduced pressure. This crude product was purified by flash chromatography on silica gel (petroleum ether / AcOEt = 4/1) to give the title Compound (2 g, 50% yield) as a yellow solid:

¹1 H NMR (400 MHz, CDCl 3): 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] hydrazono} pentane-2,4-dione

A solution of tert-butyl [2-fluoro4- (trifluoromethoxy) phenyl] carbamate (2 g, 6.8 mmol) in 300 mL HCl in AcOEt was stirred at 0 ° C for 3 h and concentrated under reduced pressure.

To a solution of this residue in 20 mL of acetic acid and 3.5 mL of concentrated hydrogen chloride solution, sodium nitrite (507 mg, 7.34 mmol) in 5 mL was added dropwise.

221

54504 Β1 water, at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. Sodium acetate (1.5 g, 18.3 mmol, 3.0 equiv.) And acetylacetone (793 mg, 7.93 mmol, 1.3 equiv.) Were then added to this reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, dried with water, EtOH / H2O (1/1) and hexane, and dried to give the title compound (920 mg, 50% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.50 (s, ZN), 2.63 (s, ZN), 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) hydrazono] pentane-2,4-dione

To a solution of 2,4-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrogen chloride solution, sodium nitrite was added dropwise (600 mg,

9.3 mmol) in 2.7 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. 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. This mixture was stirred at room temperature for 2 h, filtered, dried with water, EtOH / hhO (1/1) and hexane and dried to give the title compound (550 mg, 30% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.48 (s, ZN), 2.61 (s, ZN), 6.91-7.00 (m, 2H), 7.70-7.76 (m, 1H). 14.72 (s, 1 H).

Reference example 197

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

To a solution of 4-chloro-2-fluoroaniline (1 g, 6.87 mmol) in 9.8 mL of acetic acid and 1.6 mL of concentrated hydrogen chloride solution, sodium nitrite (568 mg, 8.24 mmol) in 2.6 mL of water was added dropwise to 0 ° C, and this mixture is stirred for 1 h at 0 ° C. Then get this one

222

54504 Sodium acetate (1.69 g, 20.6 mmol) and acetylacetone (893 mg, 8.93 mmol) were added to the reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, dried with water, EtOH / HsO (1/1) and hexane, and dried to give the title compound (1 g, 57% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.49 (s, ZN), 2.60 (s, ZN), 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] hydrazono} pentane-2,4-dione

<img file="RS54504B1_D0192.tif" />

., F 'F

2-Fluoro-5- (trifluoromethyl) aniline (2.00 g, 15.6 mmol) was added to a solution of 15.6 mL HOAc and

2.6 mL of concentrated HCl was stirred, followed by dropwise addition of sodium nitrite (0.925 g, 13.4 mmol) in 4 mL of water, at 0 ° C, and the mixture was stirred at 0 ° C for 60 min. Potassium acetate (3.28 g, 3.5 mmol) and acetylacetone (1.83 mL, 14.5 mmol) were then added dropwise. This mixture was stirred at room temperature overnight, then 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):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.53 (s, ZN), 2.64 (s, ZN), 7.26-6.30 (m, 1H), 7.39-7.42 (m, 1H), 7.99-8.01 (m, 1H) ), 14.62 (s, 1 H).

Reference example 199

3 - [(2,5-Difluorophenyl) hydrazono] pentane-2,4-dione

2,5-Difluoroaniline (2.10 g, 15.5 mmol) was added to a solution of 21.6 mL of HOAc and 3.6 mL of concentrated HCl and stirred, then sodium nitrite (1.28 g, 18.6 mmol) in 6 mL of water was added dropwise at 0 mL. ° C, and this mixture was stirred at 0 ° C for 60 min. Potassium acetate (4.56 g, 46.5 mmol) and acetylacetone (2.07 mL, 20.15) were then added dropwise.

223

54504 Β1 mmol). This mixture was stirred at room temperature overnight and filtered. The residue was dissolved in CH2Cl2, orege with water, dried over Na2SO4 and concentrated under reduced pressure to give the crude product (4.00 g, 67% yield), which was used directly in the following step:

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.51 (s, ZN), 2.62 (s, ZN), 6.79-6.83 (m, 1H), 7.09-7.15 (m, 1H), 7.43-7.47 (m, 1H) ), 14.57 (s, 1 H).

Reference example 200

3 - [(2,6-Difluorophenyl) hydrazono] pentane-2,4-dione

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 hydrogen chloride solution, sodium nitrite was added dropwise (600 mg,

9.3 mmol) in 2.7 mL of water, at 0 ° C, and this mixture was stirred at 0 ° C for 1 h. Sodium acetate (1.78 g, 21.7 mmol) and acetylacetone (1 g, 10 mmol) were then added to this reaction mixture. This mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH / NgO (1: 1) and hexane and dried to give the title compound (400 mg, 21% yield):

¹1 H NMR (400 MHz, CDCl 3): δ ppm 2.43 (s, ZN), 2.61 (s, ZN), 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

Solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (2.70 g, 8 mmol) and NH2NH2 H2O (1.94 mL, 40 mmol) in MeOH (25 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into 1 M aqueous HCl and extracted with AcOEt. This extract is washed with brine,

224

54504 Β1 dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by basic column chromatography on silica gel, eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: mp. 192-194 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 6.82 (1H, d, J = 7.9 Hz), 7.03 (1H, d, J = 1.9 Hz),

7.69 (1H, d, J = 1.9 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J = 7.9 Hz). , 12.85 (1 H, brs).

LC-MS (ESI) m / z 307 [M + H] +. Anal. Calculation. for C 14 H 9 F 3 N 4 O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.

Reference example 202

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

4-Morpholin-4-ylaniline (653 mg, 3.67 mmol) was added to a mixture of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%), at -6 ° C. When the resulting mixture reached room temperature, it was cooled to -6 ° C and sodium nitrite (253 mg, 3.67 mmol) was added over 10 min. Crushed ice (50 g) was added to this solution. This 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). This solution was stirred for 15 min, then added to 250 mL of a saturated solution of MagSO 2 in water, extracted with dichloromethane, orega water and brine, dried over anhydrous MagSO 2 and concentrated under reduced pressure to give the title compound (870 mg, 82% yield). as a brown solid:

¹1 H NMR (400 MHz, CDCl 3): δ 2.50 (ZN, s), 2.61 (ZN, 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

225

54504 Β1

<img file="RS54504B1_D0193.tif" />

Dissolve 3 - [(4-morpholin-4-ylphenyl) hydrazono] pentane-2,4-dione (500 mg, 1.73 mmol) in 10 mL of N, N-dimethylformamide dimethyl acetal. This mixture was refluxed for 4 h and then concentrated under reduced pressure to give the title compound as a brown oil, which was used in the next step without further purification:

¹1 H NMR (400 MHz, CDCl 3): δ 2.85-2.90 (ZN, m), 3 10-3.14 (ZN, 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 I -1- (2-fluoro-5-iodophenyl) -5-methoxypyridazin-4 (1H) -one

<img file="RS54504B1_D0194.tif" />

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 nitrogen. This mixture was stirred at -78 ° C for 2 h. The reaction was treated with saturated aqueous NH4Cl at -78 ° C. This mixture was diluted with saturated aqueous NaHCO 3, extracted with EtOAc, dried over Na 2 SO 4, 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 light yellow solid:

¹1 H NMR (DMSO-d 6, 300 MHz): δ ppm 2.50 (ZN, s), 3.80 (ZN, 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).

226

54504 Β1

Reference example 205

1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -N, 5-dimethyloxy-N-methyl-4-oxo-1,4-dihydropyridazine3-carboxamide

<img file="RS54504B1_D0195.tif" />

1- (2-Fluoro-4-iodophenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine3-carboxamide suspension (1.73 g, 4 mmol), pyrazole (0.408 g, 6 mmol) , SigO (0.057 g, 0.4 mmol), salicylaldoxime (0.219 g, 1.6 mmol) and CS2CO3 (2.60 g, 8 mmol) in CHsCN (8 mL) was refluxed for 6 h under Ar. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with AcOEt and recrystallized from MeOH / NgO to give the title compound (0.370 g, 25% yield) as a white solid: mp. 187-189 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.40 (ZN, s), 3.72 (ZN, s), 3.93 (ZN, 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 (ZN, m), 7.84 (1H, d, J = 2.3 Hz), 7.98 (1H, d, J = 2.6 Hz).

Anal. Calculation. for C 11 H 11 FN 5 Cl 2: 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

<img file="RS54504B1_D0196.tif" />

MeMgBr (1 M solution in THF, 2.8 mL, 2.8 mmol) was added dropwise at -78 ° C, 1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -N, 5 solution. -dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (351 mg, 0.94 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was treated with 1 M aqueous HCl and extracted with AcOEt. This extract was taken up in brine, dried over MgSO 4 and concentrated under reduced pressure.

227

54504 Β1 by pressing. The residue was purified by column chromatography on silica gel, eluting with AcOEt and recrystallized from MeOH / NgO to give the title compound (223 mg, 72% yield) as a light yellow solid: mp. 159-161 ° C;

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.69 (ZN, s), 3.93 (ZN, 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. Calculation. for C 16 H 13 FN 4 O 3: 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-ylhydrazono) butanoate

A solution of 3-aminopyridine (20 g, 210 mmol) in a 6 M solution of HCl in water (200 nnL, 1200 mmol) was cooled in an ice bath. To this solution was added dropwise a solution of sodium nitrite (18 g, 260 mmol) in water (40 mL). After stirring at 0 ° C for 5 min, this 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 0 ° C. ° C, and this mixture was stirred for 1 h at 0 ° C. This mixture was diluted with water (150 mL), extracted with AcOEt (500 mL χ 3). The combined organic layer was dried with saturated aqueous NaHCO 3 (300 mL) and brine (300 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the title compound (52 g, 97% yield) as a brown oil. :

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.50 (ZN χ 1/2, s), 3.51 (ZN h 1/2, s), 3.89 (ZN χ 1/2, s), 3.93 (ZN χ 1 / 2, s), 4.67 (2N χ 1/2, s), 4.70 (2H χ 1/2, s), 7.35-7.43 (1 Η, m), 7.67-7.74 (1Η χ 1/2, m), 7.84-7.91 (1Η χ 1/2, m), 8.41-8.49 (1H, m), 8.64-8.71 (1H, m), 12.90 (1Η χ 1/2, s). 14.76 (1 H * 1/2, brs).

Reference example 208

Methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate

228

54504 Β1

<img file="RS54504B1_D0197.tif" />

Oh₂Me

A mixture of methyl 4-methoxy-3-oxo-2- (pyridin-3-ylhydrazono) butanoate (52 g, 210 mmol) in N, N-dimethylformamide dimethyl acetal (80 mL, 600 mmol) was refluxed for 30 min. This mixture was allowed to cool to room temperature and kept at room temperature overnight. The formed crystals were collected by filtration and washed with AcOEt to give the title compound (35 g, 64% yield) as light yellow crystals:

¹1 H NMR (300 MHz, CDCl 3)₃): b ppm 3.98 (ZN, s), 3.98 (ZN, 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 hydrogen chloride

<img file="RS54504B1_D0198.tif" />

A solution of methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.7 mmol) in a 6 M solution of HCl in water (20 mL) was refluxed for 4 h. This mixture was concentrated under reduced pressure to give the title compound (2.1 g, 95% yield) as off-white crystals:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 3.98 (ZN, 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, 4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0199.tif" />

229

54504 Β1

Mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrogen chloride (1.0 g, 3.5 mmol), N, N-dimethylhydroxylamine hydrogen chloride (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. This mixture was diluted with AcOEt. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. This 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:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.41 (ZN, s), 3.71 (ZN, s), 3.98 (ZN, 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-ylpyridazin-4 (1H) -one

To 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, 1 M MeMgBr in THF (3.0 mL, 3.0 mmol), at -78 ° C. After stirring at -78 ° C for 2 h, this mixture was treated with water (0.5 mL) and stirred at room temperature for 1 h. This mixture was concentrated under reduced pressure. This residue was partitioned between CHCl 3 (25 mL) and brine. The aqueous layer was extracted with CHCl 3 (25 mL * 3). The combined organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 62% yield) as yellow crystals:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 2.70 (ZN, s), 3.97 (ZN, 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 example212

Methyl 2 - [(4-bromo-2,5-difluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate

230

54504 Β1

<img file="RS54504B1_D0200.tif" />

NaNO solution₂ (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. mL, 576 mmol). After stirring for 15 min, the resulting 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 to 0 ° C. This precipitate was collected by filtration, dried with water and dried at room temperature to give the title compound (37 g, 100% yield) as a red solid:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 3.34 (ZN, s), 3.83 (ZN, s), 4.68 (2H, s), 7.70 (1H, dd, J = 9.7, 7.0 Hz), 7.89 1 H, dd, J = 10.6, 6.1 Hz), 12.16 (1 H, s).

Reference example 213

Methyl 1- (4-bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

<img file="RS54504B1_D0201.tif" />

Br

A solution of methyl 2 - [(4-bromo-2,5-difluorophenyl) hydrazono] -4-methoxy-3-oxobutanoate (33 g, 90 mmol) in N, N-dimethylformamide dimethylacetal (72 mL) was stirred for 3 h at 110 ° C. After cooling to room temperature, this mixture was concentrated under reduced pressure. MeOH and silica gel are added to the residue. This mixture was evaporated and purified by column chromatography on silica gel, eluting with hexane / AcOEt (1/0 to 0/1) and then AcOEt / Me-OH (4/1) to give the title compound (27.9 g, 83% yield). as brown rubber:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 3.80 (ZN, s), 3.83 (ZN, 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]⁺.

231

54504 Β1

Reference example 214

1 (4Bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid

<img file="RS54504B1_D0202.tif" />

A solution of methyl 1- (4-bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (25 g, 68 mmol) and a 2 M solution of NaOH in water (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 a 6 M solution of HCl in water (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

A mixture

1- (4-Bromo-2,5-difluorophenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3 carboxylic acid (25 g, 83 mmol), NO-dimethylhydroxylamine hydrogen chloride (8.9 g, mmol ), HOBt (12 g, 91 mmol), triethylamine (24 mL, 174 mmol) and WSC (17 g, 91 mmol) in DMF (160 mL) were stirred at room temperature for 18 h. This mixture was diluted with AcOEt, orege water and brine, dried over MdbOd and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane / AcOEt (1/0 to 0/1) followed by AcOEt / MeOH (10/1), to give the title compound (11 g, 31% yield) as a yellow solid. substance: LC-MS (ESI) m / z 405 [M + H]⁺.

Reference Example 216 3-Acetyl-1- (4-bromo-2,5-difluorophenyl) -5-methoxypyridazin-4 (1H) -one

232

54504 Β1

<img file="RS54504B1_D0203.tif" />

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 to MeMgBr (1.0 M in THF, 50 mL, 50 mmol), at -78 ° C, under nitrogen. This mixture was stirred at -78 ° C for 1 h. The reaction was treated with a 1 M solution of HCl in water (70 mL), at -78 ° C. This mixture was warmed to room temperature and extracted with AcOEt. The organic layer was dried over Md 2 OH and concentrated under reduced pressure to give the title compound (3.6 g, 80% yield) as a yellow solid:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 2.50 (ZN, s), 3.80 (ZN, 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 n

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 h. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (AcOEt / hexane = 25% 100%) to give the title compound (1.13 g, 85% yield) as a colorless solid:

¹1 H NMR (300 MHz, CDCl 3): 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

<img file="RS54504B1_D0204.tif" />

233

54504 Β1

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. This mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (25 / 75-70 / 30 AcOEt / hexane) to give the title compound (0.42 g, 56% yield) as white crystals:¹1 H NMR (300 MHz, CDCl 3): δ ppm 0.68-0.75 (2H, m), 1.20-1.27 (2H, m), 3.68 (2H, s), 5.48 (1H, brs).

Reference Example 219 1- (4-Iodo-2-methoxyphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide

<img file="RS54504B1_D0205.tif" />

I II ·

L ,, N me

N

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 6 M aqueous HCl. mL). After stirring for 15 min, 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 to 0 ° C. This precipitate was collected by filtration, walnuts with water, air dried overnight. A solution of this product in N, N-dimethylformamidimethylacetal (450 mL) was refluxed for 4 h. 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.

To a suspension of these products (54 g) in THF / MeOH (1 / 1,400 mL) was added a 10% solution of NaOH in water (200 mL) and then 0 ° C. This mixture was stirred at room temperature for 45 min. To this suspension was added a 10% solution of HCl in water (200 mL), at 0 ° C. This mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and washed with 1RG2O. The obtained products (45 g) were used in the next reaction without further purification.

A mixture of these products (45 g), N-methoxymethanamine hydrogen chloride (12.4 g, 127 mmol), HOBt (18.7 g, 138 mmol), WSC (26.5 g, 138 mmol) and EtsN (48.2 mL, 346 mmol) in DMF (500 ml) was stirred at room temperature overnight. This mixture was partitioned between AcOEt and H2O, and the organic layer was washed with NaCl solution in water, dried.

234

54504 Β1 above Na₂SO₄ and evaporate. The residue was purified by column chromatography on silica gel (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.

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.38 (ZN, s), 3.70 (ZN, s), 3.88 (ZN, s), 3.89 (ZN, s), 7.23 (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

<img file="RS54504B1_D0206.tif" />

1- (4-Iodo-2-methoxyphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide suspension (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) was refluxed at 4 h under Ag. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. This extract was washed with brine, dried over MgSO 4₄ and concentrates under reduced pressure. The residue was purified by silica gel column chromatography, eluting with AcOEt / THF (1 / 0-0 / 1), to give the title compound (6.32 g, 68% yield) as a light yellow amorphous substance:

¹1 H NMR (300 MHz, CDCl 3): δ ppm 3.39 (ZN, s), 3.73 (ZN, s), 3.91 (ZN, s), 3.99 (ZN, 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-Acety [-5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one

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<img file="RS54504B1_D0207.tif" />

m

<img file="RS54504B1_D0208.tif" />

<img file="RS54504B1_D0209.tif" />

MeMgBr (1 M solution in THF, 50 mL, 50 mmol) was added dropwise at -78 ° C to N, 5-dimethoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) solution. ) phenyl] -N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (6.32 g, 16.4 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was treated with 1 M aqueous HCl and extracted with AcOEt. This extract was taken up in 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 a light yellow prism: m.p. 193196 ° C;

¹1 H NMR (300 MHz, CDCl 3)₃): b ppm 2.69 (ZN, s), 3.90 (ZN, s), 4.00 (ZN, 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), 7.77-7.78 (2H, m), 8.00 (1H, d, J = 2.3 Hz).

Anal. Calculation. 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

<img file="RS54504B1_D0210.tif" />

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 . This mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO 4₄ and concentrates under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (11.5 g, 67% yield) as a light yellow solid;

¹1 H NMR (300 MHz, DMSO-d 6): 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 , ddd, J = 9.9, 8.0, 2.1 Hz).

LC-MS (ESI) m / z 245 [M + H]⁺.

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Reference example 223

2,3-Difluoro-4-morpholin-4-ylaniline

<img file="RS54504B1_D0211.tif" />

<img file="RS54504B1_D0212.tif" />

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 h at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from JRggO / AsOEd to give the title compound (8.7 g, 86% yield) as a light red powder:

¹1 H NMR (300 MHz, DMSO-d 6): 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) hydrazono] -4-methoxy-3-oxobutanoate

<img file="RS54504B1_D0213.tif" />

A solution of NaNC&gt; 2 (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 solution of HCl in water (41 mL, 244 mmol). After stirring for 15 min, 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 to 0 ° C. This mixture was adjusted to pH 7 with 1 sa a solution of NaOH in water (200 mL). This 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

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Methyl 1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazin-3-

<td>carboxylate</td><td>FV D '' HG</td>

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 (20 mL) was stirred after 80 min at 100 [deg.] C. After cooling to room temperature, the precipitate was collected by filtration and washed with jRggO to give the title compound (4.1 g, 84% yield) as a brown powder:

¹1 H NMR (300 MHz, DMSO-d 6): 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

1- (2,3-Difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazin-3-

<td>carboxylic acid</td><td>рВ гћ (Г</td>

Methyl 1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate solution (4.1 g, 11 mmol) and 2 M NaOH solution in water (11 mL, 22 mmol), in EtOH (20 mL), was stirred at room temperature for 16 h. To this mixture was added a 1 M solution of HCl in water (21 mL). The precipitate was collected by filtration and dried under reduced pressure to give the title compound (3.8 g, 98% yield) as a white solid:

¹1 H NMR (300 MHz, DMSO-d 6): δ ppm 3.06-3.23 (4H, m), 3.66-3.82 (4H, m), 3.88 (ZN, 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]⁺.

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Reference example 227