RU2811864C1 - Pharmaceutical product containing inhibitor of sodium dependent phosphate carrier - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a pharmaceutical composition having inhibitory activity against one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and chronic renal failure or for use in the prevention or suppression of ectopic calcification, containing an effective amount of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

EFFECT: prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, chronic renal failure and the prevention or suppression of ectopic calcification, based on the use of a composition that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2.

22 cl, 49 tbl, 457 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to a pharmaceutical composition containing a dihydropyridazine-3,5-dione derivative, or a salt thereof, or a solvate of the compound or a salt. In addition, the present invention provides a method for preventing or treating a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, and a method for preventing or suppressing ectopic calcification.

BACKGROUND OF THE ART

Phosphorus is found in any cell and makes up 1% of the human body weight. This element plays an important role in maintaining life, namely in the energy metabolism of cells. The concentration of phosphorus in the blood is determined by its absorption from the gastrointestinal tract and excretion from the kidneys, as well as bone formation and bone resorption, and is established at a constant level. Phosphorus absorption in the gastrointestinal tract is primarily accomplished by the sodium-dependent phosphate transporter NaPi-IIb (SLC34A2) (Non-Patent Documents 1 and 2). Phosphorus in the blood is filtered by the renal glomeruli and reabsorbed in required quantities mainly by NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) in the renal tubule (Non-Patent Documents 1 and 3). The kidney plays a very important role in phosphorus regulation in vivo. In patients with end-stage renal disease and in patients undergoing dialysis with impaired kidney function, phosphorus accumulates in the body, which leads to an increase in the concentration of phosphorus in the blood, i.e. to hyperphosphatemia.

Hyperphosphatemia causes soft tissue calcification. In particular, vascular calcification is believed to cause cardiac dysfunction leading to patient death. Hyperphosphatemia also causes hypersecretion of parathyroid hormones, i.e. secondary hyperparathyroidism, and causes bone lesions. Therefore, hyperphosphatemia is considered as an adverse factor that worsens the prognosis and quality of life of patients with end-stage renal disease and patients undergoing dialysis.

Modern treatments for hyperphosphatemia use phosphorus scavengers to suppress phosphorus absorption in the gastrointestinal tract. The phosphorus adsorbents used are metal-free polymeric absorbents, typified by sevelamer carbonate and sevelamer hydrochloride, calcium salt preparations, typified by precipitated calcium carbonate, or metal-containing absorbents, typified by lanthanum carbonate. However, these scavengers have been reported to have undesirable side effects such as gastrointestinal disorders including constipation and diarrhea, hypercalcemia caused by rising serum calcium concentrations, and in vivo metal accumulation. In addition, these scavengers require several grams to be administered daily and therefore may have difficulty complying with treatment regimens for patients. Accordingly, the development of new treatments for hyperphosphatemia that overcome the difficulties associated with phosphorus scavengers is urgently needed.

Inhibition of NaPi-IIb, which plays an important role in the absorption of phosphorus in the gastrointestinal tract, can inhibit the absorption of phosphorus in the gastrointestinal tract, like phosphorus scavengers, reducing the concentration of phosphorus in the blood (Non-Patent Documents 2 and 4). In addition, PiT-1 (SLC20A1) and PiT-2 (SLC20A2), which like NaPi-IIb are sodium-dependent phosphate transporters, partially influence the absorption of phosphorus in the gastrointestinal tract (Non-Patent Documents 1 and 6). Therefore, a compound that inhibits NaPi-IIb, PiT-1, and PiT-2 would be expected to have a stronger inhibitory effect on phosphorus absorption and more effectively reduce blood phosphorus concentrations compared to an inhibitor of NaPi-IIb alone. However, suppression of phosphorus absorption by inhibition of these sodium-dependent phosphate transporters is based on a mechanism of action that differs from the mechanism of action of currently used phosphorus scavengers. Therefore, it can be expected that a sodium phosphate transporter inhibitor will serve as a new preventive and/or therapeutic agent for hyperphosphatemia instead of traditional phosphorus scavengers. In addition, the sodium phosphate transporter inhibitor is expected to have a preventive and/or therapeutic effect on secondary hyperparathyroidism and chronic renal failure by reducing the concentration of phosphorus in the blood (Non-Patent Document 5). Chronic kidney disease (CDK) is a disease that results in persistent kidney damage (eg, proteinuria) or persistent renal impairment (decreased GFR (glomerular filtration rate)). In 2012, in Japan, the number of patients suffering from this disease reached 13,300,000 (Non-Patent Document 7) and the development of a new drug for the prevention or treatment of chronic kidney disease was desired.

Compound NTX1942 (Patent Document 1) and the compounds described in Patent Documents 2 and 4 are described as NaPi-IIb inhibitors. In addition, a compound containing a pyridazine scaffold is described in Patent Document 3, which discloses the treatment of anemia, ischemia and hypoxia through the hypoxia-inducible factor (HIF) hydroxylase inhibitory activity of the compound.

LIST OF REFERENCES CITED

PATENT DOCUMENTS

Patent document 1: WO 2012/006475

Patent document 2: WO 2011/136269

Patent Document 3: WO 2011/048611

Patent Document 4: WO 2013/062065

NON-PATENT DOCUMENTS

Non-Patent Document 1: J Pharm Sci. 2011 Sep; 100 (9): 3719-30;

Non-Patent Document 2: J Am Soc Nephrol. 2009 Nov; 20 (11): 2348-58;

Non-Patent Document 3: Pflugers Arch. 2004 Feb; 447(5): 763-7;

Non-Patent Document 4: Am J Physiol Renal Physiol. 2011 Nov; 301(5):F1105-13;

Non-Patent Document 5: Kidney Int. 2003 Nov; 64 (5): 1653-61; And

Non-Patent Document 6: Mol Aspects Med. 2013 Apr-Jun; 34 (2-3): 386-95. Non-Patent Document 7: Japanese Journal of Nephrology, 2012; 54 (8); 1031-1189

BRIEF SUMMARY OF THE INVENTION TECHNICAL PROBLEM

There is an urgent need to develop a method to prevent or treat hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, as well as to develop a method to prevent or suppress ectopic calcification that will overcome the difficulties associated with existing phosphorus scavengers.

THE SOLUTION OF THE PROBLEM

The inventors of the present invention have conducted careful studies in light of the difficulties described above and have found for the first time that the compound of formula (I) below, which is significantly different in chemical structure from the NaPi-IIb inhibitors known in the art, has an excellent inhibitory effect on NaPi-IIb, inhibitory effect on PiT-1 or inhibitory effect on PiT-2, so that this compound is useful for the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, as well as for the prevention or suppression of ectopic calcification, and that this compound has excellent medicinal efficacy against these diseases.

In addition, according to the invention, it was found for the first time that inhibition of one or more transporters selected from PiT-1 and PiT-2 provides an excellent effect for the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification (below in the present invention referred to as "hyperphosphatemia, etc.") and for preventing or suppressing ectopic calcification.

Moreover, according to the invention, it has been found that the use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 in combination with a phosphorus scavenger provides an excellent effect for preventing or treating hyperphosphatemia, etc. P. and to prevent or suppress ectopic calcification.

In one embodiment, the present invention relates to the following pharmaceutical compositions (1-1)-(1-60):

(1-1) A pharmaceutical composition containing a compound of formula (I) or a salt thereof, or a solvate of the compound or a salt: (Formula 1)

in which R ¹ , R ⁴ and R ⁵ are as defined in any of the following paragraphs (1) to (3):

(1) R ¹ represents a hydrogen atom or C ₁ -C ₁₀ -alkyl;

R ⁴ represents a hydrogen atom, C ₁ -C ₄ -alkyl, optionally substituted by one or more Rf substituents, C ₆ -C ₁₀ -aryl, optionally substituted

one or more Rg substituents, (C ₁ -C ₆ -alkyl)carbonyl, (C ₆ -C ₁₀ -aryl)carbonyl, -C(O)NR ³⁷ R ³⁸ group, C ₃ -C ₇ -cycloalkyl or 5-8 -membered heterocycloalkyl; And

R ⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl;

(2) R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring; And

R is as defined above; And

(3) R ¹ represents a hydrogen atom or linear C ₁ -C ₁₀ -alkyl;

R ⁴ and R ⁵ , together with the carbon atom and nitrogen atom to which they are attached, form a 5-8-membered saturated heterocyclic ring,

wherein the saturated heterocyclic ring is optionally substituted with one or more R ² substituents;

R ³ is C ₁ -C ₁₀ -alkyl, optionally substituted with one or more Rh substituents, or R ³ is C ₁ -C ₄ -alkyl, substituted with Re;

R ³⁷ and R ³⁸ are each independently selected from hydrogen and C ₁ -C ₃ alkyl;

each R ² is independently selected from C1-C ₅ alkyl and a halogen atom; and/or

two or more R ² substituents on a 5-8 membered saturated heterocyclic ring can together form a C ₁ -C ₅ -alkylene, which binds the ring atoms to which it is attached;

each Rh is independently selected from a halogen atom, a (C ₁ -C ₄ -alkoxy)carbonyl and -(O(CH ₂ ) _a ) _b -C ₁ -C ₄ -alkoxy group, where a is an integer equal to 2 to 4, and b is an integer ranging from 1 to 4;

Re is C ₆ -C ₁₀ -aryl, optionally substituted with one or more Ra substituents, or 5-10 membered heteroaryl, optionally substituted with one or more Ra substituents;

each Rf is independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a carboxy group, a (C ₁ -C _b -alkoxy)carbonyl group, a C ₁ -C _b -alkoxy group, and a C ₆ -C ₁₀ -aryl group, optionally substituted by one or more substituents Rg;

each Rg is independently selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl, a C ₂ -C ₆ alkynyl and a C ₁ -C ₆ alkoxy group, wherein the alkyl, alkynyl and alkoxy group are each optionally substituted by one or more substituents selected from hydroxy group and cyano group;

each Ra is independently selected from the group consisting of a halogen atom, a hydroxy group, a nitro group, a cyano group, a (C ₁ -C ₄ -alkoxy)carbonyl, a 3-10 membered heterocycloalkyloxy group (the heterocycloalkyloxy group is optionally substituted with an optionally C ₁ -C ₄ -alkoxy-substituted C ₁ -C _4- alkyl), C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkenyl, optionally substituted with one or more R ¹⁵ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more substituent R ¹¹ , C ₁ -C ₈ -alkoxy group, optionally substituted by one or more substituent R ¹² , C ₁ -C ₄ -alkylthio group, optionally substituted with one or more substituent R ¹³ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² (where q1 is an integer equal to 1 to 4 and q2 is an integer equal to 2 to 6), group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ (where r1 is an integer equal to 1 to 4 and r2 is an integer equal to 1 to 4), the group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ (where s1 and s2 are each independently an integer equal to 2 to 4), the -C(O)NR ⁴⁷ R ⁴⁸ group, pyridinyl, pyrrolyl, the -NR ⁴⁹ R ⁵⁰ group and the -(O(CH ₂ ) _y1 ) _y2 - group O-CH ₂ -C(O)NR ⁵¹ R ⁵² (where y1 is an integer equal to 1 to 4, and y2 is an integer equal to 1 to 4);

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ are each independently selected from the group consisting of a halogen atom, a hydroxy group, a carboxy group, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, (C ₁ -C ₄ - alkoxy)C ₁ -C ₆ -alkoxy group, (C ₁ -C ₄ -alkoxy)carbonyl, -(O(CH ₂ ) _o ) _p -OH group (where o and p are each independently an integer equal to 2 to 4 ), C ₃ -C ₈ -cycloalkyl, optionally substituted with one or more hydroxy groups, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl and a -NR ³⁹ R ⁴⁰ group, where the 3-10 membered heterocycloalkyl group is optionally substituted with one or more substituent selected from the group consisting of oxo group, halogen atom, C ₁ -C ₄ -alkyl (where the alkyl group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (where an alkoxy group is optionally substituted with one or more hydroxy groups), a C ₁ -C ₄ alkoxy group, a (C ₁ -C ₄ -alkoxy)carbonyl group, a C ₁ -C ₄ -alkylthio group, a morpholine group, a (C ₁ -C ₃ -alkyl)sulfonyl group and -C(O)NR ⁵³ R ⁵⁴ ;

Ar ¹ denotes C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl, where the aryl and heteroaryl groups are each optionally substituted with 1-3 substituents independently selected from Rb, Rc and Rd;

Rb, Rc and Rd are each independently selected from the group consisting of optionally a C ₁ -C ₄ alkoxy substituted C ₁ -C ₅ alkoxy group, a halogen atom, a C ₁ -C ₁₀ alkyl optionally substituted with one or more halogen atoms, a -SF group ₅ , cyano group, hydroxy group, 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituents, C ₆ -C ₁₀ -aryl, optionally substituted with one or more R ¹⁴ substituents, and 5-10 membered heteroaryl, optionally substituted with one or more substituent R ¹⁴ ;

each R ¹⁴ is independently selected from the group consisting of a halogen atom, an oxo group, a cyano group, a nitro group, a C ₁ -C ₄ alkyl optionally substituted by one or more halogen atoms, a C ₁ -C ₄ alkoxy group optionally substituted by one or more halogen atoms, (C ₁ -C ₆ -alkoxy)carbonyl,

-NR ²⁷ R ²⁸ group, -SO ₂ NR ³⁵ R ³⁶ group, C ₁ -C ₄ alkylthio group and 5-10 membered heterocycloalkyl;

R ²⁷ and R ²⁸ are each independently selected from hydrogen and C ₁ -C ₄ -alkyl, optionally substituted with (C ₁ -C ₄ -alkoxy)carbonyl;

R ³⁵ and R ³⁶ are each independently selected from hydrogen and C ₁ -C ₄ alkyl;

R ³⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl, where the alkyl is optionally substituted with a hydroxy group or a C ₁ -C ₆ alkoxy group;

R ⁴⁰ denotes a hydrogen atom, optionally C ₁ -C ₆ -alkoxy-substituted C ₁ -C ₆ -alkyl, ((C ₁ -C ₄ -alkoxy)carbonyl) C ₁ -C ₆ -alkyl, hydroxy-substituted C ₁ -C ₆ -alkyl , C ₁ -C ₄ -alkyl substituted with a -NR ⁵⁵ R ⁵⁶ group, a -CH group ((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ (where v1 is an integer equal to 0 to 2 , and v2 is an integer equal to from 1 to 3), the -(CH ₂ ) _w -SO ₃ H group (where w is an integer equal to from 1 to 4), the -(CH ₂ ) _x1 -CH(COOH) group )-(CH ₂ ) _x2 -SO ₃ H (where x1 is an integer equal to 0 to 2 and x2 is an integer equal to 1 to 3), 3-6 membered oxacycloalkyl or -(CH ₂ ) group _t1 -O-(CH ₂ ) _t2 -C(O)NR ⁵⁸ R ⁵⁹ (where t1 and t2 are each independently an integer ranging from 1 to 3);

R ⁴¹ represents a hydrogen atom or C ₁ -C ₃ -alkyl;

R ⁴² denotes C ₁ -C ₈ -alkyl substituted by one or more hydroxy groups, or (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl;

R ⁴³ represents a hydrogen atom or C ₁ -C ₃ -alkyl;

R ⁴⁴ is C ₁ -C ₈ -alkyl substituted with one or more hydroxy groups, or

R ⁴³ and R ⁴⁴ , together with the nitrogen atom to which they are attached, can form a morpholine group;

R ⁴⁵ represents a hydrogen atom or C ₁ -C ₃ -alkyl;

R ⁴⁶ is C ₁ -C ₆ alkyl substituted with one or more hydroxy groups;

R ⁴⁷ is C ₁ -C ₃ -alkyl;

R ⁴⁸ is (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl;

R ⁴⁹ represents a hydrogen atom and C ₁ -C ₄ -alkyl;

R ⁵⁰ is -(CH ₂ ) _z -NR ⁶⁰ R ⁶¹ (z is an integer from 1 to 4, R ⁶⁰ is a hydrogen atom or C ₁ -C ₄ -alkyl and R ⁶¹ is (C ₁ -C ₃ - alkoxy)C ₁ -C ₄ -alkyl, or R ⁶⁰ and R ⁶¹ together with the nitrogen atom to which they are attached can form a morpholine group);

R ⁵¹ represents a hydrogen atom or C ₁ -C ₄ -alkyl;

R ⁵² is C ₁ -C ₈ alkyl substituted with one or more hydroxy groups; R ⁵³ and R ⁵⁴ are each independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl;

R ⁵⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl;

R ⁵⁶ is (C ₁ -C ₄ -alkyl)carbonyl;

R ⁵⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl;

R ⁵⁸ represents a hydrogen atom or C ₁ -C ₃ -alkyl; And

R ⁵⁹ denotes C ₁ -C ₈ -alkyl substituted with one or more hydroxy groups.

(1-2) The pharmaceutical composition according to paragraph (1-1), in which in the compound of formula (I) Rb optionally denotes a C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₅ -alkoxy group or a halogen atom;

Rc represents a halogen atom, a C ₁ -C ₁₀ alkyl optionally substituted with one or more halogen atoms, or a -SF ₅ group; And

Rd denotes cyano group, hydroxy group, halogen atom, C ₁ -C ₄ -alkyl, optionally substituted with one or more halogen atoms, 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituent, C ₆ -C ₁₀ -aryl, optional substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl, optionally substituted with one or more R ¹⁴ substituents.

(1-3) The pharmaceutical composition according to paragraph (1-1) or (1-2) wherein in the compound of formula (I) each Ra is independently selected from the group consisting of a halogen atom, a hydroxy group, a nitro group, a cyano group, (C ₁ -C _4- alkoxy)carbonyl, 3-10-membered heterocycloalkyloxy group, C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkenyl, optionally substituted with one or more R ¹⁵ substituents, C ₂ - A C ₁₀ -alkynyl group, optionally substituted with one or more R ¹¹ substituents, a C ₁ -C ₆ -alkoxy group, optionally substituted with one or more R ¹² substituents, and a C ₁ -C ₄ -alkylthio group, optionally substituted with one or more R ¹³ substituents;

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ are each independently selected from the group consisting of a halogen atom, a hydroxy group, a carboxy group, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, (C ₁ -C ₄ - alkoxy)carbonyl, a -(O(CH ₂ ) _o ) _p -OH group (where o and p are each independently an integer of 2 to 4), C ₃ -C ₆ -cycloalkyl, optionally substituted by one or more hydroxy groups, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR ³⁹ R ⁴⁰ group, where the 3-10 membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo group, halogen atom and C ₁ -C ₄ alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups); And

R ³⁹ and R ⁴⁰ are each independently selected from hydrogen and optionally C ₁ -C ₆ alkoxy-substituted C ₁ -C ₆ alkyl.

(1-4) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-3), wherein in the compound of formula (I), the 3-10 membered heterocycloalkyloxy group in the definition of Ra is a 3-6 membered heterocycloalkyloxy group;

3-10 membered heterocycloalkyl in the definition of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ is 3-6 membered heterocycloalkyl; And

5-10 membered heteroaryl in the definition of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ is 5-6 membered heteroaryl.

(1-5) The pharmaceutical composition according to any one of paragraphs (1-1), (1-2) and (1-4), wherein in the compound of formula (I) each Ra is independently selected from the group consisting of a halogen atom, a hydroxy group, nitro group, cyano group, (C ₁ -C ₄ -alkoxy)carbonyl, 3-6-membered heterocycloalkyloxy group (the heterocycloalkyloxy group is optionally substituted with optionally C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl), C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R ¹¹ substituents, C ₁ -C ₆ -alkoxy group, optionally substituted with one or more R ¹² substituents, C ₁ -C ₄ -alkylthio group , optionally substituted with one or more substituents R ¹³ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group - (O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, pyrrolyl, group -NR ⁴⁸ R ⁵⁰ and group -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -NR ⁵¹ R ⁵² ;

R ¹⁰ denotes a carboxy group, a 3-6 membered heterocycloalkyl, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, or a -(O(CH ₂ ) _o ) _p -OH group;

R ¹¹ denotes a hydroxy group, a carboxy group, a 5- or 6-membered heterocycloalkyl, optionally substituted by one or more oxo groups, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, a -(O(CH ₂ ) _o ) _p -OH group , C ₃ -C ₆ -cycloalkyl, optionally substituted with one or more hydroxy groups, or an NR ³⁹ R ⁴⁰ group;

R ¹² represents a halogen atom, a hydroxy group, a carboxy group, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, a (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group, (C ₁ -C ₃ -alkoxy )carbonyl, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl or -NR ³⁹ R ⁴⁰ group, where the 3-6 membered heterocycloalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo group, halogen atom, C ₁ -C ₄ -alkyl (where the alkyl group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (where the alkoxy group is optionally substituted by one or more hydroxy groups), C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholinyl, (C ₁ -C ₃ -alkyl)sulfonyl and -C(O)NR ⁵³ R ⁵⁴ ;

R ¹³ is 5- or 6-membered heterocycloalkyl; And

o and p are each independently an integer between 2 and 4.

(1-6) The pharmaceutical composition according to any one of paragraphs (1-1) (1-5), wherein in the compound of formula (I) each Ra is independently selected from the group consisting of a halogen atom, a hydroxy group, a nitro group, a cyano group, (C ₁ -C ₄ -alkoxy)carbonyl, 3-6-membered heterocycloalkyloxy group, C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R ¹¹ substituents, C _{a 1} -C ₈ alkoxy group, optionally substituted with one or more R ¹² substituents, and a C ₁ -C ₄ alkylthio group, optionally substituted with one or more R substituents;

each R ¹⁰ is independently selected from the group consisting of a carboxy group, a 3-6 membered heterocycloalkyl, a C ₁ -C ₆ alkoxy group optionally substituted by one or more hydroxy groups, and a -(O(CH ₂ ) _o ) _p -OH group;

each R ¹¹ is independently selected from the group consisting of a hydroxy group, a carboxy group, a 5- or 6-membered heterocycloalkyl group, optionally substituted by one or more oxo groups, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, a -(O(CH ₂ ) _o ) _p -OH, and C ₃ -C ₈ -cycloalkyl, optionally substituted with one or more hydroxy groups;

each R ¹² is independently selected from the group consisting of a halogen atom, a hydroxy group, a C ₁ -C ₆ -alkoxy group, optionally substituted by one or more hydroxy groups, (C ₁ -C ₃ -alkoxy)carbonyl, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl and -NR ³⁹ R ⁴⁰ group;

R ¹³ is 5- or 6-membered heterocycloalkyl; And

o and p are each independently an integer between 2 and 4.

(1-7) The pharmaceutical composition according to any one of paragraphs (1-1), (1-2), (1-4) and (1-5), wherein in the compound of formula (I) each Ra is independently selected from the group, containing a halogen atom, hydroxy group, nitro group, cyano group, C ₁ -C ₆ -alkyl, (carboxy)C ₁ -C ₈ -alkyl, (morpholino)C ₁ -C ₄ -alkyl, [HO-((CH ₂ ) _o O ) _p ]C ₁ -C ₆ -alkyl, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkyl (C ₁ -C ₆ -alkoxy group is optionally substituted by one or more hydroxy groups), C ₁ -C ₆ -alkoxy group , optionally substituted with one or more halogen atoms, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ - an alkoxy group, a C ₁ -C ₆ -alkoxy group, optionally substituted by one or more hydroxy groups, ((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkoxy group, (C ₁ -C ₈ -alkoxy)C ₁ -C ₈ -alkoxy group (C ₁ -C ₆ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₈ -alkoxy group, (3-6-membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group (the heterocycloalkyl moiety is optionally substituted with one or more substituents selected from the group consisting of oxo group, halogen atom, C ₁ -C ₄ -alkyl (where alkyl is optionally substituted with one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (where the alkoxy group is optionally substituted with one or more hydroxy groups), C ₁ -C ₄ -alkoxy, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholine group, (C ₁ -C ₃ -alkyl)sulfonyl and (di(C ₁ -C ₃ -alkyl)amino)carbonyl), C ₁ -C ₄ -alkoxy group , substituted by the group NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-(3-6-membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl)amino] C ₁ -C ₄ -alkoxy group, [N,N-di((hydroxy)C ₁ -C ₄ -alkyl)-amino]C ₁ -C ₄ -alkoxy group, [N-((C ₁ -C ₃ -alkoxy) carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (pyridinyl)C ₁ -C ₄ -alkoxy group, (pyrimidinyl)C ₁ -C ₄ -alkoxy group, (1,2,4-triazolyl)C ₁ -C ₄ -alkoxy group, [N-(hydroxy)C ₁ -C ₄ -alkyl-H-(C ₁ -C ₃ -alkyl)amino]C ₁ - C ₄ -alkoxy group, [N,N-di((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)amino]C ₁ -C ₆ -alkoxy group, [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₆ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ - alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N- (C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ alkoxy group substituted by a -NH-(CH ₂ ) _w -SO ₃ H group, C ₁ -C ₄ alkoxy group substituted by a -NH-(CH ₂ ) _x1 -CH group (COOH)-(CH ₂ ) _x2 -SO ₃ H, group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, group -NR ⁴⁹ R ⁵⁰ , group -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² , (carboxy)C ₂ -C ₆ -alkynyl, (5-6-membered heterocycloalkyl )C ₂ -C ₆ -alkynyl (heterocycloalkyl optionally substituted with one or more oxo groups), C ₂ -C ₈ -alkynyl optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl, (C ₁ -C ₆ -alkoxy)C ₂ -C ₈ -alkynyl (the alkoxy group is optionally substituted by one or more hydroxy groups), (C ₃ -C ₆ )cycloalkyl)C ₂ -C ₆ -alkynyl (the cycloalkyl is optionally substituted one or more hydroxy groups), [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₂ -C ₆ -alkynyl, ( A C ₁ -C ₃ -alkoxy)carbonyl, (morpholino)C ₁ -C ₄ -alkylthio group (the morpholine group is optionally substituted with one or more oxo groups), a 3-6 membered oxacycloalkyloxy group, or a 4-6 membered nitrogen-containing heterocycloalkyloxy group (nitrogen-containing heterocycloalkyl moiety optionally substituted with one substituent selected from (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl).

(1-8) The pharmaceutical composition according to any one of paragraphs (1-1), (1-2), (1-4), (1-5) and (1-7), wherein in the compound of formula (I) each Ra is independently selected from the group consisting of halogen atom, hydroxy group, cyano group, C ₁ -C ₆ -alkyl, (carboxy)C ₁ -C ₆ -alkyl, (morpholino)C ₁ -C ₄ -alkyl, (C ₁ -C ₈ -alkoxy)C ₁ -C ₈ -alkyl (alkoxy group substituted by one or more hydroxy groups), C ₁ -C ₆ -alkoxy group optionally substituted by one or more halogen atoms, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (morpholino)C ₁ -C ₆ -alkoxy group (the morpholine group is optionally substituted with one or two substituents selected from oxo group and C ₁ -C ₃ -alkyl), (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkoxy group (C ₁ -C ₆ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ - alkoxy(C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₈ -alkoxy group, (pyrrolidinyl)C ₁ -C ₄ -alkoxy group (pyrrolidinyl fragment optionally substituted (C ₁ -C ₄ -alkoxy)C ₁ -C ₃ -alkyl), C ₁ -C ₄ -alkoxy group substituted by the group -NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-( oxetanyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₆ -alkoxy group, group -(O(CH ₂ ) _r1 ) _r2 -(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ -alkoxy group substituted by -NH-( group CH ₂ ) _w -SO ₃ H, C ₁ -C ₄ -alkoxy group substituted by -NH-(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H, (carboxy)C ₂ -C ₆ -alkynyl, (morpholino)C ₂ -C ₆ -alkynyl, C ₂ -C ₈ -alkynyl, optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl , (C ₁ -C ₆ -alkoxy)C ₂ -C ₈ -alkynyl (the alkoxy group is replaced by one or more hydroxy groups) and (C ₁ -C ₃ -alkoxy)carbonyl.

(1-9) The pharmaceutical composition according to any one of paragraphs (1-1) (1-8), wherein in the compound of formula (I) each Ra is independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, C ₁ -C ₃ -alkyl, (carboxy)C ₁ -C ₈ -alkyl, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkyl (alkoxy group substituted by one or more hydroxy groups), C ₁ -C ₃ -alkoxy group optionally substituted by one or more halogen atoms, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (morpholino )C ₁ -C ₆ -alkoxy group, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkoxy group (the alkoxy group is optionally substituted by one or more hydroxy groups), (carboxy)C ₂ -C ₆ -alkynyl, (morpholino)C ₂ -C ₆ -alkynyl, C ₂ -C ₈ -alkynyl, optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl, (C ₁ -C ₆ - alkoxy)C ₂ -C ₈ -alkynyl (the alkoxy group is substituted by one or more hydroxy groups) and (C ₁ -C ₃ -alkoxy)carbonyl.

(1-10) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-9), wherein in the compound of formula (I), R ³ is methyl substituted with a Re group.

(1-11) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-10), wherein in the compound of formula (I), R ³ is benzyl optionally substituted with one or more Ra substituents on the benzene ring.

(1-12) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-11), wherein in the compound of formula (I), R ³ is benzyl, optionally substituted with 1-3 Ra substituents on the benzene ring.

(1-13) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-6) and (1-10) to (1-12), wherein in the compound of formula (I) Re is phenyl, optionally substituted with 1 -3 Ra substituents;

1 to 3 Ra substituents are one substituent selected from Ri, Rj and Rk, two substituents selected from combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk;

Ri represents a halogen atom or a C ₁ -C ₃ alkoxy group;

Rj represents a halogen atom, a nitro group, or a cyano group; And

Rk denotes a hydroxy group, a halogen atom, (C ₁ -C ₄ -alkoxy)carbonyl, a 5-10 membered heterocycloalkyloxy group (the heterocycloalkyloxy group is optionally substituted with optionally C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl), C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkenyl, optionally substituted with one or more R ¹⁵ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R ¹¹ substituents, C ₁ -C _{a 6} -alkoxy group, optionally substituted with one or more R ¹² substituents, a C ₁ -C ₄ -alkylthio group, optionally substituted with one or more R ¹³ substituents, a -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² group, a -( group O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, pyrrolyl, -NR ⁴⁹ R ⁵⁰ group or -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² group.

(1-14) The pharmaceutical composition according to paragraph (1-13), in which in the compound of formula (I) Rk represents a hydroxy group, a halogen atom, (C ₁ -C ₄ -alkoxy)carbonyl, a 3-6 membered heterocycloalkyloxy group (heterocycloalkyloxy group is optional optionally substituted with C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl), C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R substituents ¹¹ , C ₁ -C ₆ -alkoxy group, optionally substituted with one or more R ¹² substituents, C ₁ -C ₄ -alkylthio group, optionally substituted with one or more R ¹³ substituents, group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C( O)NR ⁴⁷ R ⁴⁸ , pyridinyl, pyrrolyl, -NR ⁴⁹ R ⁵⁰ group, or -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ^{52 group} ;

each R ¹⁰ independently represents a carboxy group, a hydroxy group, a morpholinyl group, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, or a -(O(CH ₂ ) _o ) _p -OH group;

each R ¹¹ independently represents a hydroxy group, a carboxy group, a morpholinyl group, optionally substituted by one or more oxo groups, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, a -(O(CH ₂ ) _o ) _p -OH group, C ₃ - C ₆ -cycloalkyl, optionally substituted with one or more hydroxy groups, or a -NR ³⁹ R ⁴⁰ group;

R ¹² represents a halogen atom, a hydroxy group, a carboxy group, a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, a (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group, (C ₁ -C ₃ -alkoxy )carbonyl, 3-6 membered heterocycloalkyl, 5- or 6-membered heteroaryl containing 1 nitrogen atom, or a -NR ³⁹ R ⁴⁰ group, where the 3-6 membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, halogen atom, C ₁ -C ₄ -alkyl (where the alkyl group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (where the alkoxy group is optionally substituted by one or more hydroxy groups), C ₁ -C ₄ -alkoxy groups, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio groups, morpholinyl, (C ₁ -C ₃ -alkyl)sulfonyl and -C(O)NR ⁵³ R ⁵⁴ ;

R ¹³ is morpholinyl; And

o and p are each independently an integer between 2 and 4.

(1-15) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-6) and (1-10) to (1-13), wherein in the compound of formula (I) Re is phenyl, optionally substituted with 1 -3 Ra substituents;

1 to 3 Ra substituents are one substituent selected from Ri, Rj and Rk, two substituents selected from combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk;

Ri represents a halogen atom or a C ₁ -C ₃ alkoxy group;

Rj represents a halogen atom, a nitro group, or a cyano group; And

Rk denotes a hydroxy group, a halogen atom, (C ₁ -C ₄ -alkoxy)carbonyl, a 5-10 membered heterocycloalkyloxy group, C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkenyl, optionally substituted with one or more R ¹⁵ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R ¹¹ substituents, C ₁ -C ₆ -alkoxy group, optionally substituted with one or more R ¹² substituents, or C ₁ -C ₄ - an alkylthio group, optionally substituted with one or more R ¹³ substituents.

(1-16) The pharmaceutical composition according to paragraph (1-14) or (1-15), in which in the compound of formula (I) Rk represents a hydroxy group, a halogen atom, (C ₁ -C ₄ -alkoxy)carbonyl, 3-6 -membered heterocycloalkyloxy group, C ₁ -C ₁₀ -alkyl, optionally substituted by one or more R ¹⁰ substituents, C ₂ -C ₁₀ -alkynyl, optionally substituted by one or more R ¹¹ substituents, C ₁ -C ₆ -alkoxy group, optionally substituted by one or more than one R ¹² substituent, or a C ₁ -C ₄ -alkylthio group optionally substituted with one or more R ¹³ substituents;

each R ¹⁰ is independently selected from the group consisting of a hydroxy group, a carboxy group, a morpholinyl group, a C ₁ -C ₆ alkoxy group optionally substituted by one or more hydroxy groups, and a -(O(CH ₂ ) _o ) _p -OH group;

each R ¹¹ is independently selected from the group consisting of a hydroxy group, a carboxy group, a morpholinyl group optionally substituted by one or more oxo groups, a C ₁ -C ₆ alkoxy group optionally substituted by one or more hydroxy groups, a -(O(CH ₂ ) _o ) _p -OH group , and C ₃ -C ₆ -cycloalkyl, optionally substituted by one or more hydroxy groups;

each R ¹² is independently selected from the group consisting of a halogen atom, a hydroxy group, a C ₁ -C ₆ -alkoxy group, optionally substituted by one or more hydroxy groups, (C ₁ -C ₃ -alkoxy)carbonyl, 3-6 membered heterocycloalkyl, pyridinyl, pyrrolyl and the group -NR ³⁹ R ⁴⁰ ;

R ¹³ is morpholinyl; And

o and p are each independently an integer between 2 and 4.

(1-17) The pharmaceutical composition according to paragraph (1-13) or (1-14), in which in the compound of formula (I) Rk represents a halogen atom, a hydroxy group, a C ₁ -C ₆ -alkyl, (carboxy)C ₁ - C ₈ -alkyl, (morpholino)C ₁ -C ₄ -alkyl, [HO-((CH ₂ ) _o O) _p ]C ₁ -C ₆ -alkyl, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkyl (alkoxy group optionally substituted by one or more hydroxy groups), C ₁ -C ₆ -alkoxy group optionally substituted by one or more halogen atoms, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl) -N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, C ₁ -C ₆ -alkoxy group, optionally substituted by one or more hydroxy groups, ((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkoxy group, (C ₁ -C ₈ -alkoxy)C ₁ -C ₈ -alkoxy group (C ₁ -C ₆ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ -alkoxy (C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₈ -alkoxy group, (3-6-membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group (heterocycloalkyl fragment contains from 1 to 3 heteroatoms selected from O or N, and optionally substituted with one or more substituents selected from oxo, halogen, C ₁ -C ₄ -alkyl (where the alkyl moiety is optionally substituted with one or more hydroxy groups), (C ₁ -C ₄ -alkoxy) C ₁ -C ₄ -alkyl (the alkoxy group is optionally substituted by one or more hydroxy groups), C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholine group, (C ₁ -C ₃ -alkyl)sulfonyl and (di(C ₁ -C ₃ -alkyl)amino)carbonyl), C ₁ -C ₄ -alkoxy group substituted by the group -NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-(3-6-membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di((hydroxy) C ₁ -C ₄ -alkyl)-amino]C ₁ -C ₄ -alkoxy group, [H-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-H-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (pyridinyl)C ₁ -C ₄ -alkoxy group, (pyrimidinyl)C ₁ -C ₄ -alkoxy group, (1,2,4-triazolyl)C ₁ -C ₄ - alkoxy group, [N-(hydroxy)C ₁ -C ₄ -alkyl-H-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di(C ₁ -C ₃ - alkoxy(C ₁ -C ₃ -alkyl))amino]C ₁ -C ₆ -alkoxy group, [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₆ -alkoxy group, [N-[ N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ - C ₄ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group , group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ -alkoxy group substituted by group - NH-(CH ₂ )W-SO ₃ H, C ₁ -C ₄ -alkoxy group substituted by -NH-(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H group, -(O (CH ₂ ) _s1 ) _s2 -N ^R45 -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, group -NR ⁴⁹ R ⁵⁰ , group -(O(CH ₂ ) _y1 ) _y2 - O-CH ₂ -C(O)NR ⁵¹ R ⁵² , (carboxy)C ₂ -C ₈ -alkynyl, (morpholino)C ₂ -C ₆ -alkynyl (the morpholine group is optionally substituted by one or more oxo groups), C ₂ -C ₈ -alkynyl, optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl, (C ₁ -C ₈ -alkoxy)C ₂ -C ₈ -alkynyl (alkoxy group optionally substituted with one or more hydroxy groups), (C ₃ -C ₆ -cycloalkyl)C ₂ -C ₆ -kynyl (cycloalkyl is optionally substituted with one or more hydroxy groups), (C ₁ -C ₃ -alkoxy)carbonyl, (morpholino)C ₁ -C ₄ -alkylthio group, 3-6-membered oxacycloalkyloxy group, or 3-6-membered nitrogen-containing heterocycloalkyloxy group (the nitrogen-containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl).

(1-18) The pharmaceutical composition according to paragraph (1-13), (1-14) or (1-17), in which in the compound of formula (I) Rk represents a hydroxy group, a halogen atom, a C ₁ -C ₈ alkyl, (carboxy)C ₁ -C ₆ -alkyl, (morpholino)C ₁ -C ₄ -alkyl, (C ₁ -C ₆ -alkoxy)C ₁ -C ₆ alkyl (the alkoxy group is substituted by one or more hydroxy groups), C ₁ -C ₆ -alkoxy group, optionally substituted with one or more halogen atoms, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ - C ₄ -alkoxy group, (morpholino)C ₁ -C ₆ -alkoxy group, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkoxy group (C ₁ -C ₆ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₈ -alkoxy group, (pyrrolidinyl)C ₁ -C ₄ -alkoxy group (pyrrolidinyl fragment is substituted ( C ₁ -C ₄ -alkoxy)C ₁ -C ₃ -alkyl), C ₁ -C ₄ -alkoxy group substituted by the group -NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-(oxetanyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₆ -alkoxy group, group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ -alkoxy group, substituted group -NH-(CH ₂ )W-SO ₃ H, C ₁ -C ₄ -alkoxy group substituted by group -NH-(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H, (carboxy )C ₂ -C ₈ -alkynyl, (morpholino)C ₂ -C ₆ -alkynyl, C ₂ -C ₈ -alkynyl, optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl, (C ₁ -C ₆ -alkoxy)C ₂ -C ₈ -alkynyl (the alkoxy group is substituted by one or more hydroxy groups) or (C ₁ -C ₃ -alkoxy)carbonyl.

(1-19) The pharmaceutical composition according to any one of paragraphs (1-13) (1-18), in which in the compound of formula (I) Rk represents a hydroxy group, a halogen atom, a C ₁ -C ₆ alkyl, a (carboxy)C ₁ -C ₆ -alkyl, (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkyl (alkoxy group substituted by one or more hydroxy groups), C ₁ -C ₃ -alkoxy group optionally substituted with one or more halogen atoms, [N- ((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (morpholino)C ₁ -C ₆ -alkoxy group , (C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkoxy group (C ₁ -C ₆ -alkoxy group is substituted by one or more hydroxy groups), (carboxy)C ₂ -C ₈ -alkynyl, (morpholino)C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -alkynyl, optionally substituted with one or more hydroxy groups, [HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl, (C ₁ -C ₆ -alkoxy)C ₂ -C ₈ -alkynyl (the alkoxy group is substituted by one or more hydroxy groups) or (C ₁ -C ₃ -alkoxy)carbonyl.

(1-20) The pharmaceutical composition according to any one of paragraphs (1-1) (1-19), wherein in the compound of formula (I) R ¹ , R ⁴ and R ⁵ are as defined in any of the following paragraphs from ( 1) to (3):

(1) R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl;

R ⁴ is C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms, or phenyl; And

R ⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl;

(2) R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring; And

R ⁴ is as defined above; And

(3) R ¹ represents a hydrogen atom or linear C ₁ -C ₆ alkyl;

R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached form a 5-8 membered saturated heterocyclic ring, where the saturated heterocyclic ring is optionally substituted with one or more R ² substituents.

(1-21) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-20), wherein in the compound of formula (I), R ¹ is C ₁ -C ₆ alkyl;

R ⁴ is C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms, or phenyl; And

R ⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl.

(1-22) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-20), wherein in the compound of formula (I), R ¹ represents a hydrogen atom or a linear C ₁ -C ₄ alkyl;

R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached form a 5-8 membered saturated heterocyclic ring, where the saturated heterocyclic ring is optionally substituted with one or more R ² substituents.

(1-23) The pharmaceutical composition according to any one of paragraphs (1-1) (1-20), in which in the compound of formula (I) R ¹ and R ⁵ together with the carbon atom to which they are attached form C ₃ -C ₆ -saturated carbocyclic ring; And

R ⁴ denotes C ₁ -C ₄ -alkyl.

(1-24) The pharmaceutical composition according to any one of paragraphs (1-1) (1-4), (1-10) - (1-12) and (1-20), wherein in the compound of formula (I) R ¹ , R ⁴ and R ⁵ are as defined in the following paragraph (1) or (2):

(1) R ¹ is C ₁ -C ₆ alkyl;

R ⁴ optionally represents a halogen-substituted C ₁ -C ₄ -alkyl or phenyl; And

R ⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

(2) R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring; And

R ⁴ is as defined above;

R ³ denotes C ₁ -C ₄ -alkyl substituted with a Re group;

Re is phenyl, optionally substituted with one or more Ra substituents;

each Ra is independently selected from the group consisting of a halogen atom, a C ₂ -C ₆ -alkynyl optionally substituted by one or more R ¹¹ substituents, a C ₁ -C ₆ -alkoxy group optionally substituted by one or more R ¹² substituents, 3-6 membered heterocycloalkyloxy group (the heterocycloalkyloxy group is optionally substituted with optionally C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl), -(O(CH ₂ )q ₁ ) _q2 -NR ⁴¹ R ⁴² group, -(O(CH ₂ ) _r1 ) group _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, pyrrolyl, group - NR ⁴⁹ R ⁵⁰ and the group -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² ;

R ¹¹ and R ¹² are each independently selected from the group consisting of a halogen atom, a hydroxy group, a carboxy group, a C ₁ -C ₆ alkoxy group optionally substituted by one or more hydroxy groups, a (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and the group -NR ³⁹ R ⁴⁰ , where the 3-6 membered heterocycloalkyl group is optionally substituted with one or two substituents selected from the group consisting of oxo group, halogen atom, C ₁ - C ₄ -alkyl (where the alkyl group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (where the alkoxy group is optionally substituted by one or more hydroxy groups), C ₁ -C ₄ -alkoxy , (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholine group, (C ₁ -C ₃ -alkyl)sulfonyl and -C(O)NR ⁵³ R ⁵⁴ ;

Ar ¹ denotes phenyl or 5- or 6-membered heteroaryl, where the phenyl and heteroaryl groups are each optionally substituted with 1-3 substituents independently selected from Rb, Rc and Rd;

Rb, Rc and Rd are each independently selected from halogen, C ₁ -C ₄ alkyl, optionally substituted with one or more halogen atoms, phenyl, optionally substituted with one or more R ¹⁴ substituents, and 5- or 6-membered heteroaryl, optionally substituted one or more R ¹⁴ substituents; And

each R ¹⁴ is independently selected from the group consisting of a halogen atom, a cyano group, a C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms, a C ₁ -C ₄ alkoxy group, a -SO ₂ NR ³⁵ R ³⁶ group (where R ³⁵ and R ³⁶ are each independently selected from the group consisting of a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ alkylthio group.

(1-25) The pharmaceutical composition according to any one of paragraphs (1-1) - (1-7), (1-10) - (1-12), (1-20) and (1-24), in which: compound of formula (I), each Ra is independently selected from the group consisting of a halogen atom, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino ]C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group (C ₁ -C ₄ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ -alkoxy( C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₆ -alkoxy group, (3-6-membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group (the heterocycloyl fragment is optionally substituted with one or two substituents selected from the group consisting of oxo group, halogen atom, C ₁ -C ₄ -alkyl (alkyl optionally substituted by one or more hydroxy group), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (alkoxy group optionally substituted one or more hydroxy groups), C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholine group, (C ₁ -C ₃ -alkyl)sulfonyl and (di( C ₁ -C ₃ -alkyl)amino)carbonyl), C ₁ -C ₄ -alkoxy group substituted by the group -NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-( 3-6-membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di((hydroxy)C ₁ -C ₄ -alkyl) amino]C ₁ -C ₄ -alkoxy group, [N-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group , (1,2,4-triazolyl)C ₁ -C ₄ -alkoxy group, [N-(hydroxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)amino]C ₁ -C ₆ -alkoxy group, [N,N-di(C ₁ -C ₃ - alkyl)amino]C ₁ -C ₆ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl- N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, C ₁ -C ₆ -alkoxy group, optionally substituted by one or more halogen atoms, group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ -alkoxy group substituted by group -NH-(CH ₂ ) _w -SO ₃ H, C ₁ -C ₄ - an alkoxy group substituted by a -NH-(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H group, a -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ group, group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, group -NR ⁴⁹ R ⁵⁰ , group -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² , (3-6 -membered heterocycloalkyl)C ₂ -C ₆ -alkynyl (the heterocycloalkyl fragment is optionally substituted with one oxo group), [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ - alkyl)amino]C ₂ -C ₆ -alkynyl, C ₂ -C ₈ -alkynyl, optionally substituted with one or more hydroxy groups, a 3-6 membered oxacycloalkyloxy group, or a 4-6 membered nitrogen-containing heterocycloalkyloxy group (the heterocycloalkyl moiety is optionally substituted with one substituent, selected from the group consisting of (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl).

(1-26) The pharmaceutical composition according to any one of paragraphs (1-1) (1-4), (1-10) - (1-13) and (1-20) - (1-25), in which in the connection formula (I) Re denotes phenyl, optionally substituted with 1-3 Ra substituents;

1 to 3 Ra substituents are one substituent selected from Ri, Rj and Rk, two substituents selected from combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk;

Ri represents a halogen atom;

Rj represents a halogen atom; And

Rk denotes a halogen atom, a 3-6 membered heterocycloalkyloxy group (the heterocycloalkyl moiety contains 1 heteroatom selected from O and N, and is optionally substituted with optional C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl), optionally R ¹¹ -substituted C ₂ -C ₆ -alkynyl, optionally R ¹² -substituted C ₁ -C ₆ -alkoxy group, group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , group -(O(CH ₂ ) _r1 ) _r2 -C (O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , group -NR ⁴⁹ R ⁵⁰ , or group -(O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² .

(1-27) The pharmaceutical composition according to any one of paragraphs (1-24) and (1-26), wherein in the compound of formula (I), R ¹¹ represents a morpholine group;

R ¹² is selected from the group consisting of 5-6 membered heterocycloalkyl, which contains 1 or 2 heteroatoms selected from O and N, (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group or -NR ³⁹ R ⁴⁰ group .

(1-28) The pharmaceutical composition according to any one of paragraphs (1-13), (1-14)(1-17) and (1-26), wherein in the compound of formula (I) Rk is [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group (C ₁ -C ₄ -alkoxy group is optionally substituted by one or more hydroxy groups), (C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group, (carboxy)C ₁ -C ₆ -alkoxy group, (3-6-membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group (the heterocycloalkyl fragment contains from 1 to 3 heteroatoms, which are selected from O or N, and is optionally substituted with one or two substituents selected from the oxo group, halogen atom, C ₁ -C ₄ -alkyl (where the alkyl moiety is optionally substituted with one or more hydroxy groups), (C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl (the alkoxy group is optionally substituted with one or more hydroxy groups), C ₁ -C ₄ -alkoxy group, (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₄ -alkylthio group, morpholine group, (C ₁ -C ₃ -alkyl)sulfonyl and (di(C ₁ -C ₃ -alkyl) amino)carbonyl), C ₁ -C ₄ -alkoxy group substituted by the group -NH-CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR ⁵⁷ , [N-(3-6-membered oxacycloalkyl)- N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di((hydroxy)C ₁ -C ₄ -alkyl)-amino]C ₁ -C ₄ -alkoxy group, [N-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, (1,2,4 -triazolyl)C ₁ -C ₄ -alkoxy group, [N-(hydroxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N -di(C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkyl))amino]C ₁ -C ₆ -alkoxy group, [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ - C ₆ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl) amino]C ₁ -C ₄ -alkoxy group, group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , C ₁ -C ₄ -alkoxy group substituted by the group -NH-(CH ₂ ) _w -SO ₃ H, C ₁ -C ₄ -alkoxy group substituted by the group -NH-(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H, group -(O(CH ₂ ) _s1 ) _s2 -NR ⁴⁵ -C(O)R ⁴⁶ , group -C(O)NR ⁴⁷ R ⁴⁸ , pyridinyl, group -NR ⁴⁹ R ⁵⁰ , group -( O(CH ₂ ) _y1 ) _y2 -O-CH ₂ -C(O)NR ⁵¹ R ⁵² , (3-6-membered heterocycloalkyl)C ₂ -C ₆ -alkynyl (the heterocycloalkyl fragment contains from 1 to 3 heteroatoms selected from O and N, and optionally substituted with one oxo group), [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₂ -C ₆ -alkynyl, 3-6-membered oxacycloalkyloxy group or 4-6-membered nitrogen-containing heterocycloalkyloxy group (the nitrogen-containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl).

(1-29) The pharmaceutical composition according to any one of paragraphs (1-1) (1-8), (1-10) - (1-12), (1-20) and (1-24), in which in the connection formulas (I) R ¹ , R ⁴ and R ⁵ are as defined in the following paragraph (1) or (2):

(1) R ¹ is C ₁ -C ₆ alkyl;

R ⁴ optionally represents a halogen-substituted C ₁ -C ₄ -alkyl or phenyl; And

R ⁵ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

(2) R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring; And

R ⁴ is as defined above;

R ³ denotes C ₁ -C ₄ -alkyl substituted with a Re group;

Re is phenyl, optionally substituted with one or more Ra substituents;

each Ra is independently selected from a halogen atom, an optionally R ¹¹ -substituted C ₂ -C ₆ -kynyl group, and an optionally R ¹² -substituted C ₁ -C ₆ -alkoxy group;

R ¹¹ and R ¹² are each independently selected from 5- or 6-membered heterocycloalkyl and -NR ³⁹ R ⁴⁰ ;

R ³⁹ and R ⁴⁰ are each independently selected from hydrogen and optionally C ₁ -C ₆ -alkoxy-substituted C ₁ -C ₆ -alkyl;

Ar ¹ denotes phenyl or 5- or 6-membered heteroaryl, where the phenyl and heteroaryl groups are each optionally substituted with 1-3 substituents independently selected from Rb, Rc and Rd;

Rb, Rc and Rd are each independently selected from the group consisting of a halogen atom, C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms, phenyl optionally substituted with one or more R ¹⁴ substituents, and 5- or 6-membered heteroaryl , optionally substituted with one or more R ¹⁴ substituents; And

each R ¹⁴ is independently selected from the group consisting of a halogen atom, a cyano group, a C ₁ -C ₄ alkyl optionally substituted with one or more halogen atoms, a C ₁ -C ₄ alkoxy group, a -SO ₂ NR ³⁵ R ³⁶ group (where R ³⁵ and R ³⁶ are each independently selected from the group consisting of a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ alkylthio group.

(1-30) The pharmaceutical composition according to any one of paragraphs (1-1) (1-29), wherein in the compound of formula (I), Rb represents a halogen atom;

Rc denotes a halogen atom or C ₁ -C ₄ -alkyl, optionally substituted by one or more halogen atoms; And

Rd is a halogen atom, C ₁ -C ₄ -alkyl, optionally substituted with one or more halogen atoms, phenyl, optionally substituted with one or more R ¹⁴ substituents, or 5- or 6-membered heteroaryl, optionally substituted with one or more R ¹⁴ substituents.

(1-31) The pharmaceutical composition according to any one of paragraphs (1-1) (1-12), (1-20) - (1-24), (1-29) and (1-30), in which in the connection formula (I) Re is phenyl, optionally substituted with one or more Ra substituents;

R ¹¹ and R ¹² are each independently selected from morpholinyl and the group -NR ³⁹ R ⁴⁰ ;

R ⁴ is optionally substituted with a halogen atom, C ₁ -C ₄ -alkyl or phenyl;

Ar ¹ is phenyl, pyridinyl or pyrimidinyl, wherein the phenyl, pyridinyl and pyrimidinyl groups are all optionally substituted with 1-3 substituents independently selected from Rb, Rc and Rd;

Rb represents a halogen atom;

Rc denotes a halogen atom or C ₁ -C ₄ -alkyl, optionally substituted by one or more halogen atoms; And

Rd denotes a halogen atom, C ₁ -C ₄ -alkyl, optionally substituted by one or more halogen atoms, phenyl, pyridinyl or pyrimidinyl, wherein the phenyl, pyridinyl and pyrimidinyl groups are each optionally substituted by one or more R ¹⁴ substituents.

(1-32) Pharmaceutical composition according to any of paragraphs (1-1) - (1-4), (1-10) - (1-16), (1-20) - (1-24), (1- 26) and (1-29) - (1-31), in which in the compound of formula (I) Re denotes phenyl, optionally substituted with 1-3 substituents Ra;

1 to 3 Ra substituents are one substituent selected from Ri, Rj and Rk, two substituents selected from combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk;

Ri represents a halogen atom;

Rj represents a halogen atom; And

Rk represents a hydroxy group, a C ₂ -C ₆ -alkynyl group, optionally substituted with an R ¹¹ substituent, or a C ₁ -C ₆ -alkoxy group, optionally substituted with a R ¹² substituent.

(1-33) The pharmaceutical composition according to any one of paragraphs (1-29) to (1-32), wherein in the compound of formula (I), R ¹¹ and R ¹² are each independently selected from morpholinyl, [N-((C ₁ - C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl) amino groups] and [N,N-di(C ₁ -C ₃ -alkyl) amino groups].

(1-34) The pharmaceutical composition according to any one of paragraphs (1-29) to (1-33), wherein in the compound of formula (I), R ¹¹ and R ¹² are each independently selected from morpholinyl and [N-((methoxy)ethyl )-N-(methyl)amino groups].

(1-35) Pharmaceutical composition according to any of paragraphs (1-1), (1-3) - (1-6), (1-10) - (1-12), (1-20), (1- 23), (1-24) and (1-29), in which in the compound of formula (I) R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring;

R ⁴ is C ₁ -C ₄ -alkyl;

R ³ denotes C ₁ -C ₄ -alkyl substituted with a Re group; Re is phenyl, optionally substituted with one or more Ra substituents;

each Ra is independently selected from a halogen atom and a C ₁ -C ₄ alkoxy group optionally substituted with an R ¹² substituent;

each R ¹² is independently selected from 5- or 6-membered heterocycloalkyl and -NR ³⁹ R ⁴⁰ ;

R ³⁹ and R ⁴⁰ are each independently selected from hydrogen and optionally C ₁ -C ₄ -alkoxy-substituted C ₁ -C ₄ -alkyl;

Ar ¹ denotes phenyl or 5- or 6-membered heteroaryl, where the phenyl and heteroaryl groups are each optionally substituted with 1-3 substituents independently selected from Rb, Rc and Rd;

Rb, Rc and Rd are each independently selected from a halogen atom, a C ₁ -C ₄ alkyl optionally substituted by one or more halogen atoms, and a 5- or 6-membered heteroaryl optionally substituted by one or more R substituents; And

each R ¹⁴ is independently selected from a halogen atom, a cyano group, a C ₁ -C ₄ alkyl optionally substituted by one or more halogen atoms, and a C ₁ -C ₄ alkylthio group.

(1-36) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-35), wherein in the compound of formula (I), Rb represents a halogen atom;

Rc denotes a halogen atom or C ₁ -C ₄ -alkyl, optionally substituted by one or more halogen atoms; And

Rd represents a halogen atom or a 5- or 6-membered heteroaryl, optionally substituted with one or more R ¹⁴ substituents.

(1-37) Pharmaceutical composition according to any of paragraphs (1-1) (1-12), (1-20) - (1-25), (1-29) - (1-31), (1-35 ) and (1-36), in which in the compound of formula (I) Ra is selected from the group consisting of a halogen atom, a (morpholino)C ₁ -C ₄ -alkoxy group, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, or [N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ - C ₄ -alkoxy group.

(1-38) Pharmaceutical composition according to any of paragraphs (1-1) (1-5), (1-10) - (1-16), (1-20) - (1-23), (1-26 ), (1-29), (1-32), (1-35) and (1-36), wherein in the compound of formula (I) Re is phenyl, optionally substituted with 1-3 Ra substituents;

1 to 3 Ra substituents are one substituent selected from Ri, Rj and Rk, two substituents selected from combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk;

Ri and Rj each independently represent a halogen atom; And

Rk denotes a C ₁ -C ₄ alkoxy group, optionally substituted by the substituent R ¹² .

(1-39) Pharmaceutical composition according to any one of paragraphs (1-13) (1-18), (1-20) - (1-23), (1-26) - (1-28), (1-32 ), (1-33), (1-34) and (1-38), in which in the compound of formula (I) Rk denotes a halogen atom, a (morpholino)C ₁ -C ₄ -alkoxy group, [N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group, [N,N-di(C ₁ -C ₃ - alkyl)amino]C ₁ -C ₄ -alkoxy group.

(1-40) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-39), wherein in the compound of formula (I), Rb represents a halogen atom;

Rc represents a halogen, methyl or trifluoromethyl atom;

Rd denotes a halogen atom, trifluoromethyl, phenyl, optionally substituted with 1-3 R ¹⁴ substituents and 5-6 membered heteroaryl, optionally substituted with 1-3 R ¹⁴ substituents, where heteroaryl contains from 1 to 3 heteroatoms selected from O, S and N .

(1-41) The pharmaceutical composition according to any one of paragraphs (1-1) (1-40), wherein in the compound of formula (I), R ¹⁴ is each independently selected from the group consisting of methyl, trifluoromethyl, cyano group, nitro group, halogen atom, methoxy group, ethoxy group, trifluoromethoxy group, methylthio group, methoxycarbonyl and dimethylaminosulfonyl.

(1-42) The compound according to any of paragraphs (1-1) (1-41) or a salt thereof, or a solvate of the compound or a salt, wherein in the compound of formula (I) R ¹⁴ is each independently selected from the group consisting of methyl, trifluoromethyl , a cyano group, a chlorine atom and a methylthio group.

(1-43) The pharmaceutical composition according to any one of paragraphs (1-1) (1-42), in which in the compound of formula (I) Ar ¹ denotes phenyl or 5-6 membered heteroaryl, which contains from 1 to 3 heteroatoms, selected from O, S and N, wherein phenyl and heteroaryl are substituted with one or more substituents selected from Rb, Rc and Rd.

(1-44) Pharmaceutical composition according to any of paragraphs (1-1) - (1-11), (1-20) - (1-25), (1-29) - (1-31), (1- 33) - (1-37) and (1-40) - (1-43), in which the compound of formula (I) is represented by formula (1st); (Formula 2)

in which, n1 is an integer equal to 1 to 4, n2 is an integer equal to 0 or more, ^R1 , ^R4 , ^R5 , ^Ar1 , Ra, Rb, Rc, Rd, Re are as defined in any of the paragraphs from (1-1) - (1-11), (1-20) - (1-25), (1-29) - (1-31), (1-33) - (1- 37) and (1-40) - (1-43).

(1-45) The pharmaceutical composition according to paragraph (1-44), in which in the compound described by formula (1st), n1 is 1 and n2 is 3.

(1-46) Pharmaceutical composition according to any of paragraphs (1-13) (1-23), (1-26) - (1-28), (1-30), (1-32) - (1-34) ), (1-36) and (1-38) - (1-43), in which the compound is represented by formula (I-d);

(Formula 3)

in which n1 is an integer equal to 1 to 4, n3, n4 and n5 is an integer independently equal to 0 or 1, provided that at least one of n3, n4 and n5 is 1, R ¹ , R ⁴ , R ⁵ , Ar ¹ , Rb, Rc, Rd, Re, Ri, Rj and Rk are as defined in any of paragraphs (1-13) - (1-23), (1-26) - (1 -28), (1-30), (1-32) - (1-34), (1-36) and (1-38) - (1-43).

(1-47) The pharmaceutical composition according to paragraph (1-46), in which in the compound of formula (I-d) n1 is 1.

(1-48) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-47), wherein in the compound of formula (I) Ar ¹ is 4-(trifluoromethyl)-2-(6-methylthiopyridin-3-yl )phenyl, 4-(trifluoromethyl)-2-(6-trifluoromethylpyridin-3-yl)phenyl, 4-(trifluoromethyl)-2-(4-trifluoromethylpyrimidin-5-yl)phenyl, 4-(trifluoromethyl)-2-( 6-trifluoromethylpyrimidin-4-yl)phenyl, 4-(trifluoromethyl)-2-(6-cyano-5-methylpyrimidin-4-yl)phenyl, 4-(trifluoromethyl)-2-(2-cyanopyridin-4-yl) phenyl, 4-chloro-2-(6-methylthiopyridin-3-yl)phenyl, 4-chloro-2-(6-trifluoromethylpyridin-3-yl)phenyl, 4-chloro-2-(4-trifluoromethylpyrimidin-5-yl) )phenyl, 4-chloro-2-(6-cyano-5-methylpyrimidin-4-yl)phenyl, 4-chloro-2-(6-trifluoromethylpyrimidin-4-yl)phenyl or 4-chloro-2-(2- Cyanopyridin-4-yl)phenyl.

(1-49) The pharmaceutical composition according to paragraph (1-1), comprising a compound selected from the group consisting of:

(4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide;

(4aR)-N-[2-(6-cyano-5-methylpyrimidin-4-yl)-4-(trifluoromethyl)phenyl]-1-[[2,3-difluoro-4-(2-morpholine-4- ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide;

(4aR)-N-[2-(2-cyanopyridin-4-yl)-4-(trifluoromethyl)phenyl]-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl] methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide;

6-[4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl ]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]hex-5-ynic acid;

(4aR)-1-[[2,3-difluoro-4-(3-morpholin-4-ylprop-1-ynyl)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4 -(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide;

(4aR)-1-[[4-[3-[(2R)-2,3-dihydroxypropoxy]propoxy]-2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N- [4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide;

(4aR)-1-[[4-[4-[(2R)-2,3-dihydroxypropoxy]butoxy]-2,3-Difluorophenyl]-methyl]-4-hydroxy-4a-methyl-2-oxo-N -[4-(trifluoromethyl)-2-[6-(trifluoromethyl)-pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide;

(4aR)-1-[[4-[6-[(2R)-2,3-dihydroxypropoxy]hexoxy]-2,3-difluorophenyl]-methyl]-4-hydroxy-4a-methyl-2-oxo-N -[2-(trifluoromethyl)-4-[6-(trifluoromethyl)-pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3- carboxamide;

(4aR)-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide;

(4aR)-1-[[2,3-difluoro-4-(morpholin-4-ylmethyl)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2 -[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide;

(4aR)-N-(4-bromo-3,5-difluorophenyl)-1-[(3-chloro-2-fluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro -5H-pyrrolo[1,2-b]pyridazine-3-carboxamide;

(3S)-3-tert-butyl-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-N- [4-(trifluoromethyl)-2-[6-(trifluoromethyl)-pyrimidin-4-yl]phenyl]-3H-pyridazine-5-carboxamide;

(3S)-3-tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-1-[[2,3-difluoro-4-(2-morpholine -4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide;

(3S)-3-tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-1-[[2,3-difluoro-4-(2-morpholine -4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide;

(3S)-3-tert-butyl-N-[4-chloro-2-(6-methylsulfanylpyridin-3-yl)phenyl]-1-[[2,3-difluoro-4-(2-morpholine-4- ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxamide;

(3S)-3-tert-butyl-N-[2-(6-cyano-5-methylpyrimidin-4-yl)-4-(trifluoromethyl)phenyl]-1-[[2,3-difluoro-4- (2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazin-5-carboxamide;

6-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide;

7-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-H-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;

6-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide;

7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;

4-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl ]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]butanoic acid;

5-[2,3-[difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl] phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]pentanoic acid;

6-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl ]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]hexanoic acid;

7-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl ]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]heptanoic acid;

7-[[2,3-difluoro-4-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethoxy]phenyl]-methyl]-10-hydroxy-6-methyl-8-oxo -N-[4-(trifluoromethyl)-2-[b-(trifluoromethyl)-pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;

(2S)-2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]butanedicarboxylic acid;

3-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]pentanedicarboxylic acid;

6-(2,3-difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl) -2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-en-8-carboxamide;

7-(2,3-difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl) -2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;

7-(4-(3-(dimethylamino)-2,2-dimethylpropoxy)-2,3-difluorobenzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-( 6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;

6-[[2,3-difluoro-4-[1-(2-methoxyethyl)azetidin-3-yl]oxyphenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide;

7-[[2,3-difluoro-4-[4-[methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]-4-oxobutoxy]phenyl] methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec -9-ene-9-carboxamide;

7-[[2,3-difluoro-4-[2-[2-[methyl-[(2S,3R,3R,5R)-2,3,4,5,6-pentahydroxyhexyl]-amino]ethoxy]ethoxy ]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[ 4.5]dec-9-ene-9-carboxamide;

7-[[2,3-difluoro-4-[2-[2-[2-[2-[2-methoxyethyl(methyl)amino]ethoxy]ethoxy]-ethoxy]ethoxy]phenyl]methyl]-10-hydroxy -6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9 -carboxamide; And

2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]ethanesulfonic acid;

or a salt thereof, or a solvate of the compound, or a salt.

(1-50) The pharmaceutical composition according to any one of paragraphs (1-1) (1-49), intended for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with calcification vessels.

(1-51) The pharmaceutical composition according to any one of paragraphs (1-1) (1-50), intended for use in the prevention or treatment of a disease selected from hyperphosphatemia and chronic kidney disease.

(1-52) The pharmaceutical composition according to paragraph (1-50) or (1-51), wherein the hyperphosphatemia is hyperphosphatemia in a patient suffering from chronic kidney disease.

(1-53) The pharmaceutical composition according to paragraph (1-50) or (1-51), wherein the chronic kidney disease is at stage 2 to 4 according to the GFR classification.

(1-54) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-49), intended for use in preventing or suppressing ectopic calcification.

(1-55) The pharmaceutical composition according to any one of paragraphs (1-1) to (1-49), intended for use in inhibiting one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2.

(1-56) A pharmaceutical composition containing a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, which is used for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification.

(1-57) A pharmaceutical composition containing a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, which is used to prevent or suppress ectopic calcification.

(1-58) The pharmaceutical composition according to paragraph (1-56) or (1-57), where the substance further inhibits NaPi-IIb.

(1-59) The pharmaceutical composition according to any one of paragraphs (1-56) - (1-58), where the substance inhibits NaPi-IIb, PiT-1 and PiT-2.

(1-60) The pharmaceutical composition according to any one of paragraphs (1-56) (1-59), where the substance is a low molecular weight compound.

One object of the present invention is the following pharmaceutical compositions (2-1) - (2-24).

(2-1) A pharmaceutical composition containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, which is used for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, where the composition is administered in combination with a phosphorus scavenger.

(2-2) A pharmaceutical composition for use in preventing or inhibiting ectopic calcification, containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, where the composition is administered in combination with a phosphorus scavenger .

(2-3) The pharmaceutical composition according to paragraph (2-1) or (2-2), which is a combination drug containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT- 2, and a phosphorus scavenger.

(2-4) The pharmaceutical composition according to paragraph (2-1) or (2-2), wherein the phosphorus scavenger is administered as a separate pharmaceutical composition.

(2-5) The pharmaceutical composition according to any one of paragraphs (2-1), (2-2) and (2-4), wherein a substance that inhibits one or more transporters and a phosphorus scavenger are administered simultaneously.

(2-6) The pharmaceutical composition according to any one of paragraphs (2-1), (2-2) and (2-4), wherein a substance that inhibits one or more transporters and a phosphorus scavenger are administered sequentially.

(2-7) The pharmaceutical composition according to any one of paragraphs (2-1), (2-2), (2-4) and (2-6), wherein a substance that inhibits one or more transporters is administered before or after administration of the scavenger phosphorus.

(2-8) A pharmaceutical composition containing a phosphorus scavenger intended for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, where the composition is administered in combination with a substance, which inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2.

(2-9) A pharmaceutical composition containing a phosphorus scavenger for use in preventing or inhibiting ectopic calcification, where the composition is administered in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 .

(2-10) The pharmaceutical composition according to paragraph (2-8) or (2-9), wherein a substance that inhibits one or more transporters is administered simultaneously with a phosphorus scavenger.

(2-11) The pharmaceutical composition according to paragraph (2-8) or (2-9), wherein a substance that inhibits one or more transporters is administered before or after administration of the phosphorus scavenger.

(2-12) The pharmaceutical composition according to any one of paragraphs (2-1) (2-11), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2.

(2-13) The pharmaceutical composition according to any one of paragraphs (2-1) (2-12), wherein the substance further inhibits NaPi-IIb.

(2-14) A pharmaceutical composition containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, and a phosphorus scavenger.

(2-15) The pharmaceutical composition of paragraph (2-14), intended for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification.

(2-16) The pharmaceutical composition according to paragraph (2-14), intended for use in the prevention or suppression of ectopic calcification.

(2-17) The pharmaceutical composition according to any one of paragraphs (2-1) (2-16), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2.

(2-18) The pharmaceutical composition according to any one of paragraphs (2-1) (2-16), wherein the substance further inhibits NaPi-IIb.

(2-19) The pharmaceutical composition according to any one of paragraphs (2-1) - (2-18), where the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 is a compound according to any from paragraphs (1-1) - (1-49) or a salt thereof, or a solvate of a compound or a salt.

(2-20) The pharmaceutical composition according to any one of paragraphs (2-1) to (2-19), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 is a compound, represented by any of the following formulas (1) - (5):

(Formula 4-1)

(where Ac denotes an acetyl group)

or a salt thereof, or a solvate of the compound or a salt.

(2-21) The pharmaceutical composition according to any one of paragraphs (2-1) to (2-20), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 is a compound, represented by the following formula (4):

(Formula 4-2)

or a salt thereof, or a solvate of the compound or a salt.

(2-22) The pharmaceutical composition according to any one of paragraphs (2-1) to (2-21), wherein the phosphorus scavenger is a metal-free polymer scavenger, a calcium salt preparation, or a metal salt preparation.

(2-23) The pharmaceutical composition according to any one of paragraphs (2-1) to (2-22), wherein the phosphorus scavenger is any one of a drug selected from the group consisting of bixalomer, sevelamer carbonate, sevelamer hydrochloride, precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, calcium keto acid salt, lanthanum carbonate, aluminum hydroxide, iron(III) sucrose oxyhydroxide (iron(III) oxyhydroxide in a carbohydrate shell), fermagate and iron(III) citrate hydrate.

(2-24) The pharmaceutical composition according to any one of paragraphs (2-1) to (2-23), wherein the phosphorus scavenger is sevelamer carbonate.

One object of the present invention is the following methods (3-1) - (3-6):

(3-1) A method of preventing or treating a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, comprising administering to a subject an effective amount of a substance that inhibits one or more transporters selected from NaPi- IIb, PiT-1 and PiT-2 in combination with an effective amount of phosphorus scavenger.

(3-2) A method of preventing or inhibiting ectopic calcification, comprising administering to a subject an effective amount of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 in combination with an effective amount of a phosphorus scavenger.

(3-3) The method of paragraph (3-1) or (3-2), in which a substance that inhibits one or more transporters and a phosphorus scavenger are administered as a combined drug.

(3-4) The method of paragraph (3-1) or (3-2), in which the substance that inhibits one or more transporters and the phosphorus scavenger are administered as separate pharmaceutical compositions.

(3-5) The method according to any one of paragraphs (3-1), (3-2) and (3-4), in which a substance that inhibits one or more transporters and a phosphorus scavenger are administered simultaneously.

(3-6) The method according to any one of paragraphs (3-1), (3-2) and (3-4), wherein a substance that inhibits one or more transporters is administered before or after administration of the phosphorus scavenger.

One object of the present invention is the following applications (4-1) - (4-10).

(4-1) The use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 in combination with a phosphorus scavenger for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification.

(4-2) Use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, in combination with a phosphorus scavenger, to prevent or suppress ectopic calcification.

(4-3) The use of paragraph (4-1) or (4-2), wherein the substance that inhibits one or more transporters is administered to the subject as a pharmaceutical composition separately from the phosphorus scavenger.

(4-4) The use of any one of paragraphs (4-1) to (4-3), wherein the substance that inhibits one or more transporters is administered to the subject simultaneously with the phosphorus scavenger.

(4-5) The use of any one of paragraphs (4-1) to (4-3), wherein the substance that inhibits one or more transporters is administered to the subject before or after administration of the phosphorus scavenger.

(4-6) Use of a phosphorus scavenger administered in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification.

(4-7) Use of a phosphorus scavenger administered in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 to prevent or suppress ectopic calcification.

(4-8) The use of paragraph (4-6) or (4-7), wherein the substance that inhibits one or more transporters is administered to the subject as a pharmaceutical composition separately from the phosphorus scavenger.

(4-9) The use of any one of paragraphs (4-6) to (4-8), wherein the phosphorus scavenger is administered to a subject simultaneously with a substance that inhibits one or more transporters.

(4-10) The use of any one of paragraphs (4-6) to (4-8), wherein the phosphorus scavenger is administered to the subject before or after administration of a substance that inhibits one or more transporters.

USEFUL EFFECTS OF THE INVENTION

The pharmaceutical composition of the present invention is useful as an agent for the prevention and/or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and vascular calcification.

DESCRIPTION OF IMPLEMENTATION OPTIONS

The pharmaceutical composition proposed in the present invention is described below.

Definitions

In the present invention, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. In the present invention, preferred examples of the halogen atom used as a substituent for aryl, heteroaryl and the like include fluorine atom, chlorine atom and bromine atom. In the present invention, preferred examples of the halogen atom used as a substituent for alkyl or a group partially containing alkyl (alkoxy group, alkenyl, alkylthio group, etc.) include fluorine atom. Specific examples of groups containing a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio and pentafluoroethylthio.

In the present invention, "C ₁ -C ₃ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 3 carbon atoms by removing one optional hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl and isopropyl.

In the present invention, "C ₁ -C ₄ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 4 carbon atoms by removing one optional hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and 1-methylpropyl.

In the present invention, "C ₁ -C ₅ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 5 carbon atoms by removing one optional hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl and 1-ethylpropyl .

In the present invention, "C ₁ -C ₆ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 6 carbon atoms by the removal of one arbitrary hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl , hexyl, 4-methylpentyl and 2-ethylbutyl.

In the present invention, "C ₁ -C ₈ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 8 carbon atoms by removing one optional hydrogen atom. Specific examples thereof include the groups listed above in the definition of "C ₁ -C ₆ -alkyl", as well as n-heptyl, 5-methylhexyl, 1-propylbutyl, 2-ethyl-2-methylbutyl, n-octyl, 5-methylheptyl, 2,3-dimethylhexyl, 1-methyl-1-propylbutyl and 2,2-diethylbutyl.

In the present invention, "C ₁ -C ₁₀ -alkyl" means a monovalent group formed from a linear and branched saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms by the removal of one arbitrary hydrogen atom. Specific examples thereof include the groups listed above in the definition of "C ₁ -C ₈ -alkyl", as well as 7-methyloctyl, 5-ethylheptyl, n-decyl, 8-methylnonyl, 5,5-dimethyloctyl and 4-ethyl-6- methylheptyl.

In the present invention, "linear C ₁ -C ₆ -alkyl" means a monovalent group formed from a linear saturated aliphatic hydrocarbon containing from 1 to 6 carbon atoms by the removal of one arbitrary hydrogen atom. "Linear C ₁ -C ₆ -alkyl" preferably means methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.

In the present invention, “linear C ₁ -C ₁₀ -alkyl” means a monovalent group formed from a linear saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms by the removal of one arbitrary hydrogen atom. "Linear C ₁ -C ₁₀ -alkyl" preferably means methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

In the present invention, "morpholine group" means morpholin-4-yl.

In the present invention, "(morpholino)C ₁ -C ₆ -alkyl" means a C ₁ -C ₆ -alkyl group substituted with a morpholine group. "C ₁ -C ₆ -alkyl" is as defined above. Specific examples thereof include morpholinomethyl, morpholinoethyl, morpholino-n-propyl, morpholinoisopropyl, morpholino-n-butyl, morpholinoisobutyl, morpholino-sec-butyl, morpholino-tert-butyl, morpholino-1-methylpropyl, morpholino-n-pentyl, morpholinoisopentyl, morpholino-2-methylbutyl, morpholino-1,1-dimethylpropyl, morpholino-1-ethylpropyl, morpholinohexyl, morpholino-4-methylpentyl and morpholino-2-ethylbutyl. Preferred examples thereof include morpholinomethyl.

In the present invention, "(morpholino)C ₁ -C ₄ -alkyl" means a C ₁ -C ₄ -alkyl group substituted with a morpholine group. "C ₁ -C ₄ -alkyl" is as defined above. Specific examples thereof include morpholinomethyl, morpholinoethyl, morpholino-n-propyl, morpholinoisopropyl, morpholino-n-butyl, morpholinoisobutyl, morpholino-sec-butyl, morpholino-tert-butyl, and morpholino-1-methylpropyl. Preferred examples thereof include morpholinomethyl.

In the present invention, "(oxetanyl)C ₁ -C ₄ -alkyl" means a C ₁ -C ₄ -alkyl group substituted with oxetanyl. "C ₁ -C ₄ -alkyl" is as defined above. Specific examples thereof include oxetanylmethyl, oxetanylethyl, oxetanyl-n-propyl, oxetanyl-isopropyl, oxetanyl-n-butyl, oxetanyl-isobutyl, oxetanyl-sec-butyl, oxetanyl-tert-butyl and oxetanyl-1-methylpropyl. Preferred examples thereof include oxetanylmethyl.

In the present invention, "(4-6 membered heterocycloalkyl)C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with 4-6 membered heterocycloalkyl. "C ₁ -C ₄ -alkyl" is as defined above. "4-6 membered heterocycloalkyl" means a saturated heterocyclic group consisting of 4 to 6 ring-forming atoms, containing from 1 to 3 heteroatoms selected from the group consisting of O, S and N. "(4-6 membered heterocycloalkyl)C ₁ -C ₄ -alkyl" includes "(morpholino)C ₁ -C ₄ -alkyl" and "(oxetanyl)C ₁ -C ₄ -alkyl".

In the present invention, "(carboxy)C ₁ -C ₈ -alkyl" means C ₁ -C ₈ -alkyl substituted with a carboxy group. "C ₁ -C ₈ -alkyl" is as defined above. Specific examples thereof include carboxy-n-hexyl, carboxy-n-heptyl, carboxy-5-methylhexyl, carboxy-1-propylbutyl, carboxy-2-ethyl-2-methylbutyl, carboxy-n-octyl, carboxy-5-methylheptyl, carboxy-2,3-dimethylhexyl, carboxy-1-methyl-1-propylbutyl and carboxy-2,2-diethylbutyl. Preferred examples thereof include carboxy-n-hexyl, carboxy-n-heptyl and carboxy-n-octyl.

In the present invention, "(C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkyl" means C ₁ -C ₈ -alkyl substituted with a C ₁ -C ₆ -alkoxy group. "C ₁ -C ₆ -alkoxy group" and "C ₁ -C ₈ -alkyl" are as defined above and below. Specific examples thereof include ethoxy-n-propyl, n-propoxy-n-propyl, n-butoxy-n-propyl, n-heptoxypropyl, n-propoxy-n-hexyl, n-butoxy-n-hexyl, n-propoxy- n-heptyl and n-butoxy-n-heptyl. Preferred examples thereof include n-propoxy-n-propyl and n-butoxy-n-heptyl.

In the present invention, "(C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with a C ₁ -C ₃ -alkoxy group. "C ₁ -C ₃ -alkoxy group" and "C ₁ -C ₄ -alkyl" are as defined above and below. Specific examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, methoxy-n-propyl, ethoxy-n-propyl, methoxy-n-butyl and ethoxy-n-butyl.

In the present invention, "(C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with a C ₁ -C ₄ -alkoxy group. "C ₁ -C ₄ -alkoxy group" and "C ₁ -C ₄ -alkyl" are as defined above and below. Specific examples thereof include the groups listed above in the definition of "(C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl", as well as n-butoxymethyl, n-butoxyethyl, n-butoxy-n-propyl and n-butoxy -n-butyl.

In the present invention, "(C ₁ -C ₃ -alkoxy)C ₁ -C ₆ -alkyl" means C ₁ -C ₆ -alkyl substituted with a C 1 -C 3 -alkoxy group. "C1-C3 alkoxy group" and "C ₁ -C ₆ alkyl" are as defined above and below. Specific examples thereof include the groups listed above in the definitions of "(C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl" and "(C ₁ -C ₄ -alkoxy)C ₁ -C ₄ -alkyl". Preferred examples thereof include methoxy-n-propyl.

In the present invention, "[HO-((CH ₂ ) _o O) _p ]C ₁ -C ₆ -alkyl" means C ₁ -C ₆ -alkyl substituted with a -(O(CH ₂ ) _o ) _p -OH group. C ₁ -C ₆ -alkyl is as defined above. Specific examples thereof include [HO-((CH ₂ ) ₂ O) ₃ ]propyl.

In the present invention, "C ₁ -C ₅ -alkylene" means a divalent group formed from a linear or branched saturated aliphatic hydrocarbon containing 1 to 5 carbon atoms by removing two optional hydrogen atoms. "C ₁ -C ₅ -alkylene" includes "C ₁ -C ₃ -alkylene". Specific examples thereof include -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₂ CH ₃ )-, -C(CH ₂ CH ₃ ) ₂ - and -CH(CH ₂ CH ₂ CH ₃ )-. -CH ₂ - is preferred.

In the present invention, two or more R ² substituents on a 5-8 membered saturated heterocyclic ring can together form a C ₁ -C ₅ -alkylene which binds the ring atoms to which it is attached. In this case, the saturated heterocyclic ring forms a bicyclic ring or a tricyclic ring, etc.

In the present invention, "C ₂ -C ₁₀ -alkynyl" means a monovalent group formed from a linear or branched aliphatic hydrocarbon containing from 2 to 10 carbon atoms and containing at least one triple bond (two adjacent sp-hybridized carbon atoms), by removing one arbitrary hydrogen atom. Specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, heptynyl, heptadiinyl, octinyl and octadiinyl.

In the present invention, "optionally substituted C ₂ -C ₁₀ -alkynyl" means unsubstituted C ₂ -C ₁₀ -alkynyl as described above, or C ₂ -C ₁₀ -alkynyl in which one or more hydrogen atoms are replaced by a predetermined substituent(s). ). Two or more substituents on this group may be the same or different. One carbon atom can be replaced by many substituents.

In the present invention, "C ₂ -C ₆ -alkynyl" means a monovalent group formed from a linear or branched aliphatic hydrocarbon containing from 2 to 6 carbon atoms and containing at least one triple bond (two adjacent sp-hybridized carbon atoms), by removing one arbitrary hydrogen atom. Specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl and 1-hexynyl.

In the present invention, "optionally substituted C ₂ -C ₆ -alkynyl" means unsubstituted C ₂ -C ₆ -alkynyl as described above, or C ₂ -C ₆ -alkynyl in which one or more hydrogen atoms are replaced by a predetermined substituent(s). ). Two or more substituents on this group may be the same or different. One carbon atom can be replaced by many substituents.

In the present invention, "(carboxy)C ₂ -C ₆ -kynyl" means a C2-C6 alkynyl substituted with a carboxy group. C ₂ -C ₆ -alkynyl is as defined above. Specific examples thereof include carboxyethynyl, carboxy-1-propynyl, carboxy-2-propynyl, carboxy-1-butynyl, carboxy-2-butynyl, carboxy-3-butynyl, carboxy-1-methyl-2-propynyl, carboxy-1- pentynyl, carboxy-2-pentynyl, carboxy-3-pentynyl, carboxy-4-pentynyl, carboxy-1-methyl-2-butynyl, carboxy-1-methyl-3-butynyl, carboxy-2-methyl-3-butynyl, carboxy-3-methyl-1-butynyl, carboxy-1,1-dimethyl-2-propynyl and carboxy-1-hexynyl. Preferred examples thereof include carboxy-1-pentynyl and carboxy-1-hexynyl.

In the present invention, "(C ₁ -C ₆ -alkoxy)C ₂ -C ₈ -alkynyl" means a C ₂ -C ₈ -alkynyl substituted with a C ₁ -C ₆ -alkoxy group. The C ₁ -C ₆ alkoxy group and the C ₂ -C ₈ alkynyl group are as defined above. Specific examples thereof include ethoxy-1-propynyl, propoxy-1-propynyl, butoxy-1-propynyl, propoxy-1-butynyl, propoxy-1-hexynyl, butoxy-1-hexynyl, propoxy-1-heptynyl and butoxy-1- heptynyl. Preferred examples thereof include ethoxy-1-propynyl, propoxy-1-propynyl, butoxy-1-propynyl, propoxy-1-butynyl, propoxy-1-hexynyl and butoxy-1-heptynyl.

In the present invention, "(morpholino)C ₂ -C ₆ -alkynyl" means a C ₂ -C ₆ -alkynyl substituted with a morpholine group. C ₂ -C ₆ -alkynyl is as defined above. Specific examples thereof include morpholinoethynyl, morpholino-1-propynyl, morpholino-2-propynyl, morpholino-1-butynyl, morpholino-2-butynyl, morpholino-3-butynyl, morpholino-1-pentynyl, morpholino-2-pentynyl, morpholino- 3-pentynyl, morpholino-4-pentynyl and morpholino-1-hexynyl. Preferred examples thereof include morpholino-1-propynyl, morpholino-1-butynyl and morpholino-1-heptynyl.

In the present invention, examples of "(morpholino)C ₂ -C ₆ -alkynyl substituted with oxo group(s)" include (morpholino)C ₂ -C ₆ -alkynyl optionally substituted with one or more oxo group(s). Preferred examples thereof include 3-(3-oxomorpholin-4-yl)-1-propynyl and (1,1-dioxothiomorpholin-4-yl)-1-propynyl.

In the present invention, "(3-6 membered oxacycloalkyl)C ₂ -C ₆ -alkynyl" means C ₂ -C ₆ -alkynyl substituted with 3-6 membered oxacycloalkyl. 3-6-Membered oxacycloalkyl and C ₂ -C ₆ -alkynyl are as defined herein.

In the present invention, "(oxetanyl)C ₂ -C ₆ -alkynyl" means C ₂ -C ₆ -alkynyl substituted with oxetanyl. C ₂ -C ₆ -alkynyl is as defined above. Specific examples thereof include oxetanylethynyl, oxetanyl-1-propynyl, oxetanyl-2-propynyl, oxetanyl-1-butynyl, oxetanyl-2-butynyl, oxetanyl-3-butynyl, oxetanyl-1-pentynyl, oxetanyl-2-pentynyl, oxetanyl- 3-pentynyl, oxetanyl-4-pentynyl and oxetanyl-1-hexynyl. Preferred examples thereof include oxetanyl-1-propynyl, oxetanyl-1-butynyl and oxetanyl-1-pentynyl.

In the present invention, "(pyrrolidino)C ₂ -C ₆ -alkynyl" means a C ₂ -C ₆ -alkynyl substituted with a pyrrolidine group. C ₂ -C ₆ -alkynyl is as defined above. Specific examples thereof include pyrrolidinoethynyl, pyrrolidino-1-propynyl, pyrrolidino-2-propynyl, pyrrolidino-1-butynyl, pyrrolidino-2-butynyl, pyrrolidino-3-butynyl, pyrrolidino-1-pentynyl, pyrrolidino-2-pentynyl, pyrrolidino- 3-pentynyl, pyrrolidino-4-pentynyl and pyrrolidino-1-hexynyl. Preferred examples thereof include pyrrolidino-1-propynyl.

In the present invention, "(C ₃ -C ₆ -cycloalkyl)C ₂ -C ₆ -alkynyl" means C ₂ -C ₆ -alkynyl substituted with _{C 3} -C ₆ -cycloalkyl. C ₃ -C ₆ -cycloalkyl and C ₂ -C ₆ -alkynyl are as defined above. Specific examples thereof include cyclopropylethynyl, cyclobutylethynyl, cyclopentylethynyl, cyclohexylethynyl, cyclopropyl-1-propynyl, cyclobutyl-1-propynyl, cyclopentyl-1-propynyl, cyclohexyl-1-propynyl, cyclopropyl-1-butynyl, cyclobutyl-1-butynyl, cyclopentyl- 1-butynyl and cyclohexyl-1-butynyl. Preferred examples thereof include cyclopropylethynyl, cyclobutylethynyl, cyclopentylethynyl, cyclopropyl-1-propynyl, cyclobutyl-1-propynyl and cyclopentyl-1-propynyl.

In the present invention, “[HO-((CH ₂ ) _o O) _p ]C ₂ -C ₈ -alkynyl” means C ₂ -C ₈ -alkynyl substituted with a -(O(CH ₂ ) _o ) _p -OH group. C ₂ -C ₈ -alkynyl is as defined above. Specific examples thereof include [HO-((CH ₂ ) ₂ O) ₃ ]propynyl and [HO-((CH ₂ ) ₂ O) ₂ ]propynyl.

In the present invention, "[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₂ -C ₆ -alkynyl” means C ₂ -C ₆ -alkynyl, substituted with N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl) amino group. In this context, "[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-H-(C ₁ -C ₃ -alkyl)amino group]" and "C ₂ -C ₆ -alkynyl" are as defined herein. Specific examples include [N-(2-methoxyethyl)-N-(methyl)amino]ethynyl, [N-(2-methoxy-1,1-dimethylethyl)-N-(methyl)amino]ethynyl, and [N-(2 -methoxy-2-methyl-1-propyl)-N-(methyl)amino]ethynyl.

In the present invention, "C ₁ -C ₃ -alkoxy group" means a C ₁ -C ₃ -alkyl-O- group. In this context, C ₁ -C ₃ -alkyl is as defined above. Specific examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group and a 2-propoxy group.

In the present invention, "C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkyl-O- group. In this context, C ₁ -C ₄ -alkyl is as defined above. Specific examples thereof include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and t-butoxy group.

In the present invention, "C ₁ -C ₅ -alkoxy group" means a C ₁ -C ₅ -alkyl-O- group. In this context, C ₁ -C ₅ -alkyl is as defined above. Specific examples thereof include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group and 1-pentyloxy group.

In the present invention, "C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkyl-O- group. In this context, C ₁ -C ₆ -alkyl is as defined above. Specific examples thereof include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, 1-pentyloxy group and 1-hexyloxy group.

In the present invention, "C ₁ -C ₈ -alkoxy group" means a C ₁ -C ₈ -alkyl-O- group. Specific examples thereof include the groups listed above in the definition of “C ₁ -C ₆ alkoxy groups,” as well as the 1-heptyloxy group and the 1-octyloxy group.

In the present invention, "(carboxy)C ₁ -C ₈ -alkoxy group" means a C ₁ -C ₈ -alkoxy group substituted by one carboxy group. "C ₁ -C ₈ -alkoxy group" is as defined above. Specific examples thereof include carboxy-n-propoxy group, carboxy-n-butoxy group, carboxy-n-pentoxy group and carboxy-n-hexoxy group.

In the present invention, "(morpholino)C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkoxy group substituted with a morpholine group. "C ₁ -C ₆ -alkoxy group" is as defined above. Specific examples thereof include morpholinomethoxy group, morpholinoethoxy group, morpholino-1-propoxy group, morpholino-2-propoxy group, morpholino-n-butoxy group, morpholino-isobutoxy group, morpholino-sec-butoxy group, morpholino-tert-butoxy group, morpholino-1-pentyloxy group and morpholino-1- hexyloxy group. Preferred examples thereof include the morpholinoethoxy group.

In the present invention, "(3-6 membered oxacycloalkyl)C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with 3-6 membered oxacycloalkyl. "C ₁ -C ₄ -alkoxy group" is as defined above. 3-6 membered oxacycloalkyl means a saturated heterocyclic group consisting of 3-6 ring-forming atoms containing 1 or 2 (preferably 1) oxygen atoms. "(3-6 membered oxacycloalkyl)C ₁ -C ₄ -alkoxy group" includes (oxiranyl)C ₁ -C ₄ -alkoxy group, (oxetanyl)C ₁ -C ₄ -alkoxy group and (oxolanyl)C ₁ -C ₄ -alkoxy group . Specific examples thereof include oxiranylmethoxy group, oxiranylethoxy group, oxiranyl-1-propoxy group, oxiranyl-n-butoxy group, oxetanylmethoxy group, oxetanylethoxy group, oxetanyl-1-propoxy group, oxetanyl-n-butoxy group, oxolanylmethoxy group, oxolanylethoxy group, oxolanyl-1- propoxy group and oxolanyl-n- butoxy group. Preferable examples thereof include oxolanyl methoxy group, oxiranyl methoxy group and oxetanyl methoxy group.

In the present invention, "3-6 membered oxacycloalkyloxy group" means 3-6 membered oxacycloalkyl-O-. "3-6 membered oxacycloalkyl" is as defined above. Specific examples thereof include an oxiranyloxy group, an oxetanyloxy group, an oxolanyloxy group, and an oxanyloxy group. Oxetanyloxy group, oxolanyloxy group or oxanyloxy group is preferred.

In the present invention, "4-6 membered nitrogen heterocycloalkyloxy group" means 4-6 membered nitrogen heterocycloalkyl-O-. "4-6 membered nitrogen-containing heterocycloalkyl" means a saturated heterocyclic group consisting of 4-6 ring-forming atoms containing 1 or 2 nitrogen atoms. Specific examples thereof include a pyrrolidinyloxy group and an azetidinyloxy group.

In the present invention, "(pyridinyl)C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with pyridinyl. "C ₁ -C ₄ -alkoxy group" is as defined above. Specific examples thereof include a pyridinylmethoxy group, a pyridinylethoxy group, a pyridinyl-1-propoxy group and a pyridinyl-n-butoxy group. Preferred examples thereof include a pyridinylmethoxy group.

In the present invention, "(pyrimidinyl)C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with pyrimidinyl. "C ₁ -C ₄ -alkoxy group" is as defined above. Specific examples thereof include a pyrimidinylmethoxy group, a pyrimidinylethoxy group, a pyrimidinyl-1-propoxy group and a pyrimidinyl-n-butoxy group. Preferred examples thereof include a pyrimidinylmethoxy group.

In the present invention, "(1,2,4-triazolyl)C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with 1,2,4-triazolyl. "C ₁ -C ₄ -alkoxy group" is as defined above. Specific examples thereof include 1,2,4-triazolylmethoxy group, 1,2,4-triazolylethoxy group, 1,2,4-triazolyl-1-propoxy group and 1,2,4-triazolyl-n-butoxy group. Preferred examples thereof include the 1,2,4-triazolylethoxy group.

In the present invention, "(3-6 membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkoxy group substituted with 3-6 membered heterocycloalkyl. 3-6 membered heterocycloalkyl means a saturated heterocyclic group consisting of 3-6 ring-forming atoms, containing from 1 to 3 heteroatoms selected from the group consisting of O, S and N. A C ₁ -C ₆ -alkoxy group is as defined higher. "(3-6 membered heterocycloalkyl)C ₁ -C ₆ -alkoxy group" includes (morpholino)C ₁ -C ₆ -alkoxy group, (3-6 membered oxacycloalkyl)C ₁ -C ₄ -alkoxy group, (pyrrolidinyl)C ₁ -C ₄ -alkoxy group, (azetidinyl)C ₁ -C ₄ -alkoxy group and (piperidinyl)C ₁ -C ₄ -alkoxy group. Specific examples thereof include morpholinomethoxy group, morpholinoethoxy group, morpholino-1,1-dimethylethoxy(morpholino-tert-butoxygroup), morpholino-1-methylethoxy(morpholino-2-propoxygroup), tetrahydrofuranylmethoxygroup, pyrrolidinylmethoxygroup, pyrrolidinylethoxygroup, azetidinylmethoxygroup, azetidinylethoxygroup, piperidinylmethoxy group, piperidinylethoxy group, piperazinylmethoxy group, piperazinylethoxy group.

In the present invention, "(5- or 6-membered heteroaryl)C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with a 5- or 6-membered heteroaryl. A 5- or 6-membered heteroaryl and a C ₁ -C ₄ alkoxy group are as defined in the present invention. Specific examples thereof include the 1,2,4-triazolylethoxy group.

In the present invention, "(C ₁ -C ₆ -alkoxy)C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkoxy group substituted with a C ₁ -C ₆ -alkoxy group. "C ₁ -C ₆ -alkoxy group" is as defined above. "(C ₁ -C ₆ -alkoxy)C ₁ -C ₆ -alkoxy group" includes "(C ₁ -C ₄ -alkoxy)C ₁ -C ₆ -alkoxy group", "C ₁ -C ₃ -alkoxy(C ₁ - C ₄ -alkoxy)", etc. Specific examples thereof include methoxymethoxy group, methoxyethoxy group, ethoxymethoxy group, ethoxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxymethoxy group, propoxyethoxy group, propoxypropoxy group, methoxybutoxy group, ethoxybutoxy group, propoxybutoxy group, butoxymethoxy group, butoxyethoxy group, butoxypropoxy group group, butoxybutoxy group, methoxypentoxy group, ethoxy and pentoxy group, propoxypentoxy group, butoxypentoxy group, pentoxymethoxy group, pentoxyethoxy group, pentoxypropoxy group , pentoxybutoxy group, pentoxypentoxy group, methoxyhexoxy group, ethoxyhexoxy group, propoxyhexoxy group, butoxyhexoxy group, pentoxyhexoxy group, hexoxymethoxy group, hexoxyethoxy group, hexoxypropoxy group, hexoxybutoxy group, hexoxypentoxy and hexoxyhexoxy group. Preferred examples thereof include propoxybutoxy, propoxypentoxy and propoxyhexoxy.

In the present invention, "(C ₁ -C ₆ -alkoxy)C ₁ -C ₈ -alkoxy group" means a C ₁ -C ₈ -alkoxy group substituted with a C ₁ -C ₆ -alkoxy group. "C ₁ -C ₆ -alkoxy group" and "C ₁ -C ₈ -alkoxy group" are as defined above. Specific examples thereof include the groups listed above in the definition of "(C ₁ -C ₆ -alkoxy)C ₁ -C ₆ -alkoxy groups", as well as hexoxyheptyloxy and hexoxyoctyloxy.

In the present invention, "(C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkoxy))C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with C ₁ -C ₃ -alkoxy(C ₁ -With ₄ -alkoxy group). "C ₁ -C ₃ -alkoxy(C ₁ -C ₄ -alkoxy group)" means a C ₁ -C ₄ -alkoxy group substituted with a C ₁ -C ₃ -alkoxy group. "C ₁ -C ₄ -alkoxy group" and "C ₁ -C ₃ -alkoxy group" are as defined above. Specific examples thereof include a methoxyethoxyethoxy group, an ethoxyethoxyethoxy group and a methoxyethoxymethoxy group.

In the present invention, “[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group” means C ₁ -C ₄ -alkoxy group substituted with N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl) amino group. In this context, "[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino group]" means an amino group substituted with (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl. (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl are as defined above. Specific examples of "[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy groups" include [N- methoxyethyl)-N-(methyl)amino]ethoxy group, [N-(methoxy-1,1-dimethylethyl)-N-(methyl)amino]ethoxy group and [N-(-methoxy-2-methyl-1-propyl)- N-(methyl)amino]ethoxy group.

In the present invention, "[N-(3-6-membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted by N-( 3-6-membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl) amino group. In this context, "[N-(3-6 membered oxacycloalkyl)-N-(C ₁ -C ₃ -alkyl)amino group]" means an amino group substituted with 3-6 membered oxacycloalkyl and C ₁ -C ₃ -alkyl. 3-6 membered oxacycloalkyl is as defined in the present invention. Specific examples thereof include [N-tetrahydrofuranyl-N-(methyl)amino]ethoxy group, [N-tetrahydropyranyl-N-(methyl)amino]ethoxy group and [N-oxetanyl-N-(methyl)amino]ethoxy group.

In the present invention, [N,N-di((hydroxy)C ₁ -C ₄ -alkyl)-amino]C ₁ -C ₄ -alkoxy group means a C ₁ -C ₄ -alkoxy group substituted by N,N-di((hydroxy) With ₁ -C ₄ -alkyl)-amino group. "[N,N-di((hydroxy)C ₁ -C ₄ -alkyl)-amino group]" means an amino group substituted by two (hydroxy)C ₁ -C ₄ -alkyl groups. (Hydroxy)C ₁ -C ₄ -alkyl means C ₁ -C ₄ -alkyl substituted with one hydroxy group. Specific examples thereof include the [N,N-di(2-hydroxyethyl)amino]ethoxy group.

In the present invention, "[N-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group" means C ₁ -C ₄ -alkoxy group substituted with N-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl) amino group. [N-((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl-N-(C ₁ -C ₃ -alkyl)amino group] means an amino group substituted with ((C ₁ -C ₃ -alkoxy) carbonyl)C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkyl. "((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkyl" means C ₁ -C ₃ -alkyl substituted with (C ₁ -C ₃ -alkoxy)carbonyl. Specific examples thereof include the [N-((methoxy)carbonyl)methyl-N-methylamino]ethoxy group.

In the present invention, "[N-(hydroxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with N -(hydroxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl) amino group. "N-(hydroxy)C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino group" means an amino group substituted with (hydroxy)C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl. "(Hydroxy)C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with one hydroxy group. Specific examples thereof include the [N-(2-hydroxyethyl)-N-methylamino]ethoxy group.

In the present invention, "[N,N-di((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)amino]C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkoxy group substituted with N, N-di((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl) amino group. "N,N-di((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)amino group" means an amino group substituted with two (C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl groups. "(C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl" is as defined above. Specific examples thereof include the [N,N-di((methoxy)ethoxy)amino]ethoxy group.

In the present invention, "[N,N-di(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₆ -alkoxy group" means a C ₁ -C ₆ -alkoxy group substituted by N,N-di(C ₁ -C ₃ -alkyl) amino group. "N,N-di(C ₁ -C ₃ -alkyl)amino group" means an amino group substituted by two C ₁ -C ₃ -alkyl groups. "C ₁ -C ₆ -alkoxy group" and "C ₁ -C ₃ -alkyl" are as defined above. Specific examples thereof include 3-[N,N-di(methyl)amino]-2,2-dimethylpropoxy.

In the present invention, "[N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl) amino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl) amino group. The C ₁ -C ₄ alkoxy group is as defined above. "N-[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl) amino group " means an amino group substituted with [N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl. C ₁ -C ₃ -alkyl is as defined above. "[N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl) amino group. "N-(C ₁ -C ₄ -alkyl)carbonyl-N-(C ₁ -C ₃ -alkyl)amino group" means an amino group substituted with (C ₁ -C ₄ -alkyl)carbonyl and C ₁ -C ₃ -alkyl. Specific examples thereof include the 2-[N-[2-(N-acetyl-N-(methyl)amino)ethyl]-N-(methyl)amino]ethoxy group.

In the present invention, "[N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino]C ₁ -C ₄ -alkoxy group" means a C ₁ -C ₄ -alkoxy group substituted with an N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino group. The C ₁ -C ₄ alkoxy group is as defined above. "N-[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl-N-(C ₁ -C ₃ -alkyl)amino group" means an amino group substituted with [N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl and C ₁ -C ₃ -alkyl. C ₁ -C ₃ -alkyl is as defined above. "[N-(C ₁ -C ₄ -alkyl)carbonylamino]C ₁ -C ₄ -alkyl" means C ₁ -C ₄ -alkyl substituted with an N-(C ₁ -C ₄ -alkyl)carbonylamino group. "N-(C ₁ -C ₄ -alkyl)carbonylamino group" means an amino group substituted with (C ₁ -C ₄ -alkyl)carbonyl. Specific examples thereof include the 2-[N-[2-(acetylamino)ethyl]-N-(methyl)amino]ethoxy group.

In the present invention, "C ₁ -C ₃ -alkylthio group" means a C ₁ -C ₃ -alkyl-S- group. In this context, C ₁ -C ₃ -alkyl is as defined above. Specific examples thereof include methylthio group, ethylthio group, n-propylthio group and isopropylthio group.

In the present invention, "C ₁ -C ₄ -alkylthio group" means a C ₁ -C ₄ -alkyl-S- group. In this context, C ₁ -C ₄ -alkyl is as defined above. Specific examples thereof include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group and t-butylthio group.

In the present invention, "(morpholino)C ₁ -C ₄ -alkylthio group" means a C ₁ -C ₄ -alkylthio group substituted with a morpholine group. The C ₁ -C ₄ -alkylthio group is as defined above. Specific examples thereof include a morpholinomethylthio group, a morpholinoethylthio group, a morpholino-n-propylthio group, a morpholino-isopropylthio group, a morpholino-n-butylthio group, a morpholino-isobutylthio group, and a morpholino-tert-butylthio group. Preferred examples thereof include the morpholinoethylthio group.

In the present invention, "(5- or 6-membered heterocycloalkyl)C ₁ -C ₄ -alkylthio group" means a C ₁ -C ₄ -alkylthio group substituted with a 5- or 6-membered heterocycloalkyl group. A 5- or 6-membered heterocycloalkyl and a C ₁ -C ₄ alkylthio group are as defined in the present invention. "(5- or 6-membered heterocycloalkyl)C ₁ -C ₄ -alkylthio group" includes "(morpholino)C ₁ -C ₄ -alkylthio group". Preferred examples thereof include the 2-morpholinoethylthio group.

In the present invention, "(C ₁ -C ₆ -alkyl)carbonyl" means a C ₁ -C ₆ -alkyl-C(O)- group. In this context, C ₁ -C ₆ -alkyl is as defined above. "(C ₁ -C ₆ -alkyl)carbonyl" includes "(C ₁ -C ₄ -alkyl)carbonyl". Specific examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1- ethylpropylcarbonyl, hexylcarbonyl, 4-methylpentylcarbonyl and 2-ethylbutylcarbonyl.

In the present invention, "di(C ₁ -C ₃ -alkyl)amino)carbonyl" means a carbonyl substituted with a di(C ₁ -C ₃ -alkyl)amino group. "Di(C ₁ -C ₃ -alkyl)amino group" means an amino group substituted with two C ₁ -C ₃ -alkyl groups. Specific examples thereof include dimethylaminocarbonyl and diethylaminocarbonyl.

In the present invention, "(C ₁ -C ₃ -alkyl)sulfonyl" means a C ₁ -C ₃ -alkyl-SO ₂ - group. In this context, C ₁ -C ₃ -alkyl is as defined above. Specific examples thereof include methylsulfonyl, ethylsulfonyl and n-propylsulfonyl. Preferred examples thereof include methylsulfonyl.

In the present invention, "(C ₁ -C ₆ -alkoxy)carbonyl" means a C ₁ -C ₆ -alkyl-O-C(O)- group. In this context, C ₁ -C ₆ -alkyl is as defined above. Specific examples thereof include the groups listed below in the definition of "(C ₁ -C ₄ -alkoxy)carbonyl", as well as n-pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, 4-methylpentyloxycarbonyl and 2-ethylbutoxycarbonyl.

In the present invention, "(C ₁ -C ₄ -alkoxy)carbonyl" means a C ₁ -C ₄ -alkyl-O-C(O)- group. In this context, C ₁ -C ₄ -alkyl is as defined above. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and 1-methylpropoxycarbonyl.

In the present invention, "(C ₁ -C ₃ -alkoxy)carbonyl" means a C ₁ -C ₃ -alkyl-O-C(O)- group. In this context, C ₁ -C ₃ -alkyl is as defined above. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl and isopropoxycarbonyl.

In the present invention, "((C ₁ -C ₄ -alkoxy)carbonyl)C ₁ -C ₆ -alkyl" means C ₁ -C ₆ -alkyl substituted with (C ₁ -C ₄ -alkoxy)carbonyl. In this context, (C ₁ -C ₄ -alkoxy)carbonyl and C ₁ -C ₆ -alkyl are as defined above. Specific examples thereof include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, n-propoxycarbonylmethyl and isopropoxycarbonylmethyl. Preferred examples thereof include methoxycarbonylmethyl and methoxycarbonylethyl.

In the present invention, "((C ₁ -C ₃ -alkoxy)carbonyl)C ₁ -C ₃ -alkoxy group" means a C ₁ -C ₃ -alkoxy group substituted with a (C ₁ -C ₃ -alkoxy)carbonyl group. In this context, (C ₁ -C ₃ -alkoxy)carbonyl and C ₁ -C ₃ -alkyl are as defined above. Specific examples thereof include a methoxycarbonylmethoxy group, a methoxycarbonylethoxy group, an ethoxycarbonylmethoxy group, an ethoxycarbonylethoxy group, an n-propoxycarbonylmethoxy group, and an isopropoxycarbonylmethoxy group. Preferable examples thereof include methoxycarbonylmethoxy group and methoxycarbonylethoxy group.

In the present invention, "C ₆ -C ₁₀ -aryl" means a monovalent aromatic hydrocarbon ring group. Examples of C ₆ -C ₁₀ -aryl include phenyl, 1-naphthyl and 2-naphthyl.

In the present invention, "(C ₆ -C ₁₀ -aryl)carbonyl" means a C ₆ -C ₁₀ -aryl-C(O)- group. In this context, C ₆ -C ₁₀ -aryl is as defined above. Specific examples thereof include phenylcarbonyl, 1-naphthylcarbonyl and 2-naphthylcarbonyl.

As used herein, “5 to 10 membered heteroaryl” means an aromatic ring group of 5 to 10 ring-forming atoms containing one or more (eg, 1 to 5, preferably 1 to 3) heteroatoms. The ring may be a monocyclic or bicyclic ring. Examples of "5-10 membered heteroaryl" include "5 or 6 membered heteroaryl". Specific examples of "5-10 membered heteroaryl" include thienyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, quinolinyl, isoquinolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, indolyl, imidazolyl, furil , thioxazolyl, pyrrolyl, tetrazolyl, oxopyrimidinyl, naphthyl, benzodioxinyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzothienyl, benzofuranyl, benzopyranyl and triazolyl.

As used herein, "5- or 6-membered heteroaryl" means an aromatic ring group of 5 or 6 ring-forming atoms containing one or more (for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2) heteroatoms. Specific examples thereof include thienyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, furyl, thioxazolyl and triazolyl.

In the present invention, "C ₃ -C ₆ -saturated carbocyclic ring" means a cycloalkane ring containing from 3 to 6 ring-forming carbon atoms, and includes, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane. In formula (I), R ¹ and R ⁵ together with the carbon atom to which they are attached can form a C ₃ -C ₆ saturated carbocyclic ring. In this case, the C ₃ -C ₆ saturated carbocyclic ring forms a spirane ring. In formula (I), the C ₃ -C ₆ saturated carbocyclic ring formed by R ¹ and R ⁵ together with the carbon atom to which they are attached is preferably cyclobutane, cyclopentane or cyclohexane, particularly preferably cyclobutane or cyclopentane.

In the present invention, "5-8 membered saturated heterocyclic ring" means a saturated heterocyclic group consisting of 5-8 ring-forming atoms containing one N as a heteroatom. Specific examples thereof include pyrrolidine, piperidine, azepane and azocane, and preferably include pyrrolidine and piperidine.

In the present invention, n is preferably an integer of 1 to 3, particularly preferably 1 or 2.

When Re is C ₆ -C ₁₀ -aryl, optionally substituted with one or more Ra substituents, or 5-10 membered heteroaryl, optionally substituted with one or more Ra substituents, C ₆ -C ₁₀ -aryl is preferably phenyl and 5-10- the heteroaryl member is preferably indolyl. Preferably, unless R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached form a 5-8 membered saturated heterocyclic ring, Re is preferably phenyl.

In the present invention, AR ¹ (or AR ¹⁰¹ ) preferably means phenyl, naphtil, foulil, tienil, pyridazinyl, pyrazinyl, thiazolil, oxasolil, isotiazolil, tiadiazolil, oxadiazolil, Izoxazolil, piraisolil, chinolinyl, tanoline, benzotiazolyl, benzoisolis Dazolil, Piridinyl, pyrimidinyl or indolyl. These groups are all optionally substituted with 1-3 substituents independently selected from the group consisting of Rb (or Rz ¹ ), Rc (or Rz ² ) and Rd (or Rz ³ ). If R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 5-8 membered saturated heterocyclic ring or in the case of a compound described by formula (II), Ar ¹ (or Ar ¹⁰¹ ) is more preferably phenyl, furyl, pyridinyl or pyrimidinyl.

Unless R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached form a 5-8 membered saturated heterocyclic ring, Ar ¹ is preferably phenyl, pyridinyl or pyrimidinyl.

In the present invention, Rd (or Rz ³ ) is preferably phenyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, furyl, thiadiazolyl, thioxazolyl, oxadiazolyl, pyrrolyl, tetrazolyl, oxo pyrimidinyl , naphthyl, benzodioxinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indazolyl, benzothienyl, benzofuranyl, benzopyranyl, piperazinyl, piperidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, dioxopyrrolidinyl, dioxopiperidinyl, dioxotetrahydr opyrimidinyl, oxoimidazolidinyl or dioxoimidazolidinyl. These groups are all optionally substituted with one or more R ¹⁴ substituents. If R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached form a 5-8 membered saturated heterocyclic ring or in the case of a compound described by formula (II), Rd (or Rz ³ ) is preferably phenyl, thienyl , pyridinyl, pyrimidinyl, quinolinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, more preferably phenyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl or piperidinyl. If R ⁴ and R ⁵ together with the carbon atom and nitrogen atom to which they are attached do not form a 5-8 membered saturated heterocyclic ring, Rd (or Rz ³ ) is preferably phenyl, pyridinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, piperidinyl or piperazinyl, more preferably phenyl, pyridinyl or pyrimidinyl.

In the present invention, "C ₃ -C ₆ -cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group containing from 1 to 6 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present invention, "C ₃ -C ₇ -cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group containing from 1 to 7 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the present invention, “3 to 10 membered heterocycloalkyl” means a saturated heterocyclic group consisting of 3 to 10 ring-forming atoms, containing from 1 to 3 heteroatoms selected from O, S and N. The heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Specific examples of "3-10 membered heterocycloalkyl" include the groups listed below in the definition of "4-10 membered heterocycloalkyl" as well as oxiranyl.

In the present invention, "4-10 membered heterocycloalkyl" means a saturated heterocyclic group consisting of 4-10 ring-forming atoms, containing from 1 to 3 heteroatoms selected from O, S and N. The heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Examples of "4 to 10 membered heterocycloalkyl" include "5 to 10 membered heterocycloalkyl", "5 to 8 membered heterocycloalkyl", "6 to 8 membered heterocycloalkyl" and "5 or 6 membered heterocycloalkyl". Specific examples of "4-10 membered heterocycloalkyl" include the groups listed below in the definition of "5-10 membered heterocycloalkyl" as well as oxetanyl, azetidinyl and 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl.

As used herein, "5 to 10 membered heterocycloalkyl" means a saturated heterocyclic group of 5 to 10 ring-forming atoms containing 1 to 3 heteroatoms selected from O, S and N. The heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Examples of "5-10 membered heterocycloalkyl" include "6-8 membered heterocycloalkyl" and "5- or 6-membered heterocycloalkyl". Specific examples of "5-10 membered heterocycloalkyl" include piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro [3.3]heptyl and 2-thia-6-azaspiro[3.3]heptyl.

In the present invention, "4-8 membered heterocycloalkyl" means a saturated heterocyclic group consisting of 4-8 ring-forming atoms, containing from 1 to 3 heteroatoms selected from O, S and N. The heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Specific examples of the "4-8 membered heterocycloalkyl" include those described as specific examples of the "5-8 membered heterocycloalkyl".

In the present invention, "5-8 membered heterocycloalkyl" means a saturated heterocyclic group consisting of 5-8 ring-forming atoms, containing from 1 to 3 heteroatoms selected from O, S and N. The heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Examples of "5-8 membered heterocycloalkyl" include "6-8 membered heterocycloalkyl" and "5- or 6-membered heterocycloalkyl". Specific examples of the "5-8 membered heterocycloalkyl" include those described as specific examples of the "6-8 membered heterocycloalkyl".

In the present invention, "6-8 membered heterocycloalkyl" means a saturated heterocyclic group consisting of 6 to 8 ring-forming atoms, containing from 1 to 3 heteroatoms selected from O, S and N. Heterocycloalkyl may be a monocyclic, bicyclic or spirocyclic heterocycloalkyl. Specific examples thereof include piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl and 2-thia-6- azaspiro[3.3]heptyl and preferably include 2-oxo-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl and 2-thia-6-azaspiro[3.3]heptyl.

As used herein, "3 to 6 membered heterocycloalkyl" means a saturated heterocyclic group of 3 to 6 ring-forming atoms containing 1 to 3 heteroatoms selected from O, S and N. Specific examples thereof include the groups listed below in the definition "5- or 6-membered heterocycloalkyl", also oxetanyl.

As used herein, "4 to 6 membered heterocycloalkyl" means a saturated heterocyclic group of 4 to 6 ring-forming atoms containing from 1 to 3 heteroatoms selected from O, S and N. Specific examples thereof include the groups listed below in the definition "5- or 6-membered heterocycloalkyl".

As used herein, "5- or 6-membered heterocycloalkyl" means a saturated heterocyclic group of 5 or 6 ring-forming atoms containing 1 to 3 heteroatoms selected from O, S and N. Specific examples of heterocycloalkyl include piperazinyl, piperidinyl, morpholinyl , thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl and tetrahydrofuranyl.

In the present invention, "3-6 membered oxacycloalkyl" means a saturated heterocyclic group consisting of 3-6 ring-forming atoms containing 1 or 2 oxygen atoms. Specific examples thereof include oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

In the present invention, "3-10 membered heterocycloalkyloxy group" means a 3-10 membered heterocycloalkyl-O- group. In this context, 3-10 membered heterocycloalkyl is as defined above. Specific examples thereof include an oxiranyloxy group, an oxetanyloxy group, a tetrahydrofuranyloxy group and a tetrahydropyranyloxy group. The tetrahydropyranyloxy group is preferred.

In the present invention, "5-10 membered heterocycloalkyloxy group" means a 5-10 membered heterocycloalkyl-O- group. In this context, 5-10 membered heterocycloalkyl is as defined above. The "5-10 membered heterocycloalkyloxy group" is preferably a tetrahydropyranyloxy group or a tetrahydrofuranyloxy group, particularly preferably a tetrahydropyranyloxy group.

In the present invention, "4-6 membered heterocycloalkyloxy group" means a 4-6 membered heterocycloalkyl-O- group. In this context, 4-6 membered heterocycloalkyl is as defined above.

In the present invention, "5- or 6-membered heterocycloalkyloxy group" means a 5- or 6-membered heterocycloalkyl-O- group. In this context, 5- or 6-membered heterocycloalkyl is as defined above.

In the present invention, "3-6 membered heterocycloalkyloxy group" means a 3-6 membered heterocycloalkyl-O- group. In this context, 3-6 membered heterocycloalkyl is as defined above.

In the present invention, "3-10 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "5-8 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", "4 -8-membered heterocycloalkyl", "3-6-membered heterocycloalkyl", "5- or 6-membered heterocycloalkyl", "5-10-membered heterocycloalkyloxy", "3-6-membered heterocycloalkyloxy", "5- or 6- "membered heterocycloalkyloxy group" or "4-6 membered nitrogen-containing heterocycloalkyloxy group" may be substituted with predetermined substituent(s). In this case, substituent(s) are attached to each of these groups via a carbon atom or heteroatom, forming a heterocycloalkyl ring or heterocycloalkyloxy group.

If Re is a 5- to 10-membered heteroaryl optionally substituted with one or more Ra substituents, this group contains, for example, 1 to 3 nitrogen atoms as ring-forming groups.

If Ra represents a 5-10 membered heterocycloalkyloxy group, a 3-6 membered heterocycloalkyloxy group or a 4-6 membered heterocycloalkyloxy group, the group contains, for example, 1 to 3 oxygen atoms or 1 nitrogen atom as ring-forming groups. Examples of the heterocycloalkyloxy group include tetrahydropyranyloxy group, oxetanyloxy group, pyrrolidinyloxy group, azetidinyloxy group and piperidinyloxy group.

If R ¹⁰ is 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl or 5 or 6 membered heterocycloalkyl, this group contains, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-forming groups. If R ¹⁰ is 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, the group is preferably morpholinyl, homomorpholinyl, thiomorpholinyl , piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl or tetrahydrofuranyl, more preferably morpholinyl. These groups are all optionally substituted with substituent(s) described as substituents for the corresponding heterocycloalkyl group.

If R ¹¹ denotes 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl or 5- or 6-membered heterocycloalkyl, this group contains, for example, from 1 to 3 heteroatoms selected from a nitrogen atom and oxygen atoms as ring-forming groups.

If R ¹¹ is C ₃ -C ₆ -cycloalkyl, 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl or 5- or 6-membered heterocycloalkyl, this group is preferably cyclopentyl, morpholinyl, pyrrolidinyl, homomorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl or tetrahydrofuranyl, more preferably cyclopentyl, morpholinyl or pyrrolidinyl. These groups are all optionally substituted with substituent(s) described as substituents for the corresponding cycloalkyl or heterocycloalkyl group.

If R ¹² is 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl or 5 or 6 membered heterocycloalkyl, this group contains, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-forming groups.

If R ¹² represents a 5- to 10-membered heteroaryl or a 5- or 6-membered heteroaryl, this group contains, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-forming members groups. It is also preferable if this group contains 1 nitrogen atom as a heteroatom.

If R ¹² is 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 5- or 6-membered heterocycloalkyl, 5-10 membered heteroaryl, or 5- or 6-membered heteroaryl, this group is preferably morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, thiomorpholinyl, oxetanyl, pyridinyl or 1,2,4-triazolyl, more preferably morpholinyl, tetrahydrofuranyl, pyridinyl or 1,2, 4-triazolyl. These groups are all optionally substituted with substituent(s) described as substituents for the corresponding heterocycloalkyl or heteroaryl group.

If R ¹³ denotes 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl or 5- or 6-membered heterocycloalkyl, this group contains, for example, from 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-forming groups.

If R ¹³ is 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl or 5- or 6-membered heterocycloalkyl, this group is preferably morpholinyl, homomorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, azetidinyl or tetrahydropyranyl, more preferably morpholinyl. These groups are all optionally substituted with substituent(s) described as substituents for the corresponding heterocycloalkyl group.

If R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁵ is C ₃ -C ₆ -cycloalkyl, optionally substituted with one or more hydroxy groups, 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6- member heterocycloalkyl (these heterocycloalkyl groups are all optionally substituted by one or more substituents selected from those described as substituents for the corresponding heterocycloalkyl group, such as oxo group, halogen atom, C ₁ -C ₄ -alkyl (where C ₁ -C ₄ - an alkyl group is optionally substituted with one or more hydroxy groups)), or a 5-10 membered heteroaryl, this cycloalkyl group is preferably cyclopentyl, cyclohexyl or cyclobutyl (these groups are all optionally substituted with one or more hydroxy groups); this heterocycloalkyl group is preferably tetrahydrofuranyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, homopiperazinyl, azetidinyl or tetrahydropyranyl (all of these groups are optionally substituted with one or more substituents described above); and this heteroaryl group is preferably pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazolyl. The cycloalkyl group is more preferably cyclopentyl (this group is optionally substituted with one or more hydroxy groups); the heterocycloalkyl group is more preferably tetrahydrofuranyl, pyrrolidinyl or morpholinyl (all of these groups are optionally substituted by one or more of the substituents described above); and the heteroaryl group is more preferably pyridinyl.

If Ar ¹ represents a 5-10 membered heteroaryl or a 5-6 membered heteroaryl, the group contains, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-forming groups. Ar ¹ is optionally substituted with 1-3 substituents selected from Rb, Rc and Rd, i.e. optionally substituted with Rb, Rc or Rd, with and Rc, Rc and Rd, or Rb and Rd, or with Rb, Rc and Rd.

If Rd denotes a 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituents, this group contains, for example, 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom as ring-forming groups.

If Rd denotes 5-10 membered heteroaryl or 5-6 membered heteroaryl, optionally substituted with one or more R ¹⁴ substituents, this group contains, for example, from 1 to 3 heteroatoms selected from a nitrogen atom and a sulfur atom as ring-forming groups .

If R ¹⁴ denotes a 5-10 membered heterocycloalkyl, this group contains, for example, 1 to 3 heteroatoms selected from a nitrogen atom and an oxygen atom as ring-forming groups. When R ¹⁴ is a 5-10 membered heterocycloalkyl, this group is preferably 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl or 2-thia- 6-azaspiro[3.3]heptyl, especially preferably 2-oxa-6-azaspiro[3.3]heptyl.

If Re is a C ₆ -C ₁₀ -aryl (eg phenyl) optionally substituted with one or more Ra substituents, or a 5-10 membered heteroaryl optionally substituted with one or more Ra substituents, this group contains, for example, 1 to 4 Ra substituents, preferably from 1 to 3 Ra substituents.

If R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁵ represents a C ₁ -C ₆ alkoxy group, optionally substituted by one or more hydroxy groups, this group is substituted, for example, with 1 to 5 hydroxy groups, preferably 1 to 4 hydroxy group.

If R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁵ is a 5-10 membered heterocycloalkyl, optionally substituted with one or more oxo groups, this group is substituted, for example, with 1 to 3 oxo groups, preferably 1 or 2 oxo groups.

If R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁵ is C ₃ -C ₆ -cycloalkyl, optionally substituted with one or more hydroxy groups, this group is substituted, for example, with 1 to 3 hydroxy groups, preferably 1 or 2 hydroxy groups .

Where Rb, Rc or Rd is 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituents, C ₆ -C ₁₀ -aryl, optionally substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl, optionally substituted one or more R ¹⁴ substituents, this group contains, for example, from 1 to 4 R ¹⁴ substituents, preferably from 1 to 3 R ¹⁴ substituents.

When R ⁴ is C ₆ -C ₁₀ -aryl, optionally substituted with one or more Rg substituents, this C ₆ -C ₁₀ -aryl group is preferably phenyl.

In the group -NR ³⁹ R ⁴⁰ , R ³⁹ preferably represents a hydrogen atom or C ₁ -C ₃ alkyl, more preferably methyl. R ⁴⁰ preferably denotes C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-substituted C ₁ -C ₄ -alkyl, the group -CH((CH ₂ ) _v1 COOR ⁵⁷ )-(CH ₂ ) _v2 -COOR, 4- 6-membered heterocycloalkyl, -(CH ₂ ) _w -SO ₃ H group, or -(CH ₂ ) _x1 -CH(COOH)-(CH ₂ ) _x2 -SO ₃ H group, more preferably methoxyethyl, 2-methoxy-1 ,1-dimethylethyl, 2-methoxy-2-methyl-1-propyl, group -C ₂ H ₃ -(COOH) ₂ , group -C ₃ H ₅ -(COOH) ₂ , oxetanyl, methyl, group -C ₂ H ₄ -SO ₃ H, or the group -CH(COOH)-CH ₂ -SO ₃ H. Examples of the -NR ³⁹ R ⁴⁰ group include N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)- N-(C ₁ -C ₃ -alkyl) amino group. In this context, "[N-((C ₁ -C ₃ -alkoxy)C ₁ -C ₄ -alkyl)-N-(C ₁ -C ₃ -alkyl)amino group]" is as defined above. The -NR ³⁹ R ⁴⁰ group is preferably N-(2-methoxyethyl)-N-(methyl)amino, [N-(2-methoxy-1,1-dimethylethyl)-N-(methyl)amino]ethoxy, [N -(2-methoxy-2,2-dimethylethyl)-N-(methyl)amino]ethoxy group, -NH-CH(COOH)-CH ₂ (COOH) group, -NH-CH(CH ₂ COOH)-CH ₂ group COOH, N-oxetanyl-N-methylamino group, dimethylamino group, -NH-C ₂ H ₄ -SO ₃ H group or -NH-CH(COOH)-CH ₂ -SO ₃ H group.

In the group -(O(CH ₂ ) _q1 ) _q2 -NR ⁴¹ R ⁴² , q1 is preferably 2 and q2 is preferably an integer ranging from 2 to 5. R ⁴¹ is preferably hydrogen or methyl and R ⁴² is preferably C ₁ -C ₆ -alkyl (preferably n-hexyl) substituted with 1 to 5 hydroxy groups (preferably 5 hydroxy groups), or methoxyethyl.

In the group -(O(CH ₂ ) _r1 ) _r2 -C(O)NR ⁴³ R ⁴⁴ , r1 is preferably 2 or 3 and r2 is preferably 1. R ⁴³ is preferably methyl. R ⁴⁴ is preferably C ₁ -C ₆ -alkyl (preferably n-hexyl) substituted with 1 to 5 hydroxy groups (preferably 5 hydroxy groups).

A compound of formula (I) in which R ¹ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -C ₆ saturated carbocyclic ring can be described by the following formula (I-a) or (Ib):

(Formula 5)

Group -(CH ₂ ) _q -, in which q is equal to 0 means a single bond.

In the present invention, the compound of formula (I) in which R ³ is C ₁ -C ₄ alkyl substituted with a Re group can be described by formula (I-c) below. In the present invention, a compound of formula (I) in which R ³ is a C ₁ -C ₄ alkyl substituted with a Re group, Re is substituted with 1 to 3 Ra substituents and 1 to 3 Ra substituents are one substituent selected from group comprising Ri, Rj and Rk, two substituents selected from the combinations of Ri and Rj, Ri and Rk and Rj and Rk, or three substituents Ri, Rj and Rk, can be described by the formula (Id) given below.

(Formula 6)

In formula (Ic), n1 is an integer ranging from 1 to 4; n2 is an integer equal to 0 or more; and R ¹ , R ⁴ , R ⁵ , Ar ¹ , Ra, Rb, Rc, Rd and Re are as defined in any of paragraphs (1-1) - (1-48), (2-1) - (2-25), (3-1) - (3-12), (4-1) - (4-12), (5-1) - (5-12) and (6-1) - (6 -10). In formula (Id), n3, n4 and n5 are all independently integers equal to 0 to 1, provided that at least one of n3, n4 and n5 is 1; n1 is as defined above; R ¹ , R ⁴ , R ⁵ , Ar ¹ , Rb, Rc, Rd, Re, Ri, Rj and Rk are as defined in any of paragraphs (1-1) - (1-48), (2- 1) - (2-25), (3-1) - (3-12), (4-1) - (4-12), (5-1) - (5-12) and (6-1) - (6-10).

In the present invention, n2 is preferably an integer from 1 to 4, more preferably an integer from 1 to 3.

In the present invention, the expression "optionally substituted with" or "substituted with" means "optionally substituted with one substituent" or "substituted with one substituent" respectively, unless the number of substituents is specified (for example, "one or more", "1 to 3", "1 or 2", "2" or "1"). For example, “B optionally substituted with A” and “B substituted with A” mean “B optionally substituted with one A” and “B substituted with one A”, respectively.

In the present invention, examples of salts of the compound represented by formula (I), (I-a), (I-b), (I-e) or (I-d) include acid addition salts and base addition salts. Examples of acid addition salts include: hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate and sulfate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate; and carboxylates such as acetate, citrate, malate, tartrate, succinate, salicylate, maleate, fumarate, benzoate, malonate, glycolate, oxalate, glucuronate, adipate, glutarate, ketoglutarate and hippurate. Examples of addition salts with bases include: alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt and tetraalkylammonium salt; and amino acid salts such as lysine salt, arginine salt, glycine salt, valine salt, threonine salt, serine salt, proline salt and alanine salt. These salts are all prepared by reacting the compound with an acid or base used in pharmaceutical production.

In the present invention, the compound represented by formula (I), (I-a), (I-b), (I-c) or (I-d) or a salt thereof may be anhydrous or may form a solvate such as a hydrate. In this context, "solvate" means a solid formed by a compound molecule and a solvent molecule and is, for example, a hydrate formed with water as a solvent. The non-hydrate solvate includes a solid containing alcohol (eg, methanol, ethanol and n-propanol), dimethylformamide, and the like.

The compound described by formula (I), (I-a), (I-b), (I-c) or (I-d), and its salt may be in the form of several tautomers, for example, keto and enol forms, imine and enamine forms and mixtures thereof. Such tautomers exist in solution as a tautomeric mixture. In solid form, one of the tautomers usually predominates. Although the present invention may describe one of the tautomers, all tautomers of the compound proposed in the present invention are included in the scope of the present invention.

Also included within the scope of the present invention are all stereoisomers (e.g., enantiomers and diastereoisomers (including cis- and trans-geometric isomers)) of the compounds of formula (I), (I-a), (I-b), (I-e) or (I-d), racemates isomers and other mixtures. The compound of the present invention may contain, for example, one or more asymmetric atoms. The compound of the present invention includes racemic mixtures, mixtures of diastereoisomers and enantiomers of such compounds.

The compound of formula (I), (I-a), (I-b), (I-c) or (I-d) can be obtained in free form. In this case, the free compound can be converted by standard procedures into a salt that the compound can form, or into a hydrate, or into a solvate of the compound, or into a salt.

Alternatively, the compound of formula (I), (I-a), (I-b), (I-c) or (I-d) can be prepared as a salt, hydrate or solvate of the compound. In this case, this form can be converted into the free form of the compound using standard methods.

Each element forming a compound of formula (I), (Ia), (Ib), (Ic) or (Id) may be any isotope. Within the scope of the present invention is a compound of formula (I), (Ia), (Ib), (Ic) or (Id) containing such an isotope. An isotope in a compound means a variant of an element in which at least one atom is replaced by an atom with the same atomic number (same number of protons) and different mass number (same number of protons and neutrons). Examples of the isotope contained in the pharmaceutical drug of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom and chlorine atom, including ^2H , ^3H , ^13C , ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ R, ³² R, ³⁵ S, ¹⁸ F and ³⁶ Cl. In particular, a radioisotope such as ³ H or ¹⁴ C that undergoes radioactive decay is useful, for example, in in vivo histological studies of the distribution of a pharmaceutical drug or compound. Stable isotopes rarely change in content without decay, and they are also not radioactive. Therefore, such stable isotopes can be used without concern. The isotope in a compound serving as an active ingredient in the pharmaceutical drug of the present invention can be changed according to standard procedures by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.

A compound of formula (I), (I-a), (I-b), (I-c) or (I-d) may be in the form of a prodrug. Also included within the scope of the present invention is such a prodrug of a compound of formula (I), (I-a), (I-b), (I-c) or (I-d). In this context, a "prodrug" as used herein means a derivative of a compound of formula (I), (I-a), (I-b), (I-c) or (I-d), which upon administration is converted to a compound of formula (I), (I-a) , (I-b), (I-c) or (I-d) or a pharmaceutically acceptable salt thereof by enzymatic or non-enzymatic degradation under physiological conditions. The prodrug may be inactive when administered to a patient. The prodrug is converted in vivo to the active compound of formula (I), (I-a), (I-b), (I-c) or (I-d).

The prodrug is converted, for example, into the desired pharmaceutical composition at a certain pH value or by the action of an enzyme. A prodrug is typically a compound that forms a free acid in vivo and a compound containing a hydrolyzable ester group. Such a hydrolyzable ester group is, for example, but not limited to, a group described by the formula -COORx, in which Rx is selected from the group consisting of C ₁ -C ₄ -alkyl, C ₂ -C ₇ -alkanoyloxymethyl, 1-(C ₄ -C ₉ -alkanoyloxy)ethyl, 1-methyl-1-(C ₅ -C ₁₀ -alkanoyloxy)-ethyl, (C ₃ -C ₆ -alkoxy)carbonyloxymethyl, 1-[(C ₄ -C ₇ -alkoxy) carbonyloxy]ethyl, 1-methyl-1-[(C ₅ -C ₈ -alkoxy)carbonyloxy]ethyl, N-[(C ₃ -C ₉ -alkoxy)carbonyl]aminomethyl, 1-(N-[(C ₄ - C ₁₀ -alkoxy)carbonyl]amino)-ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, [N,N-di(C ₁ -C ₂ -alkyl)amino]C ₂ -C ₃ -alkyl (for example, N,N-dimethylaminoethyl), (carbamoyl)C ₁ -C ₂ -alkyl, [N,N-di(C ₁ -C ₂ -alkyl)carbamoyl]C ₁ -C ₂ -alkyl, (piperidino )C ₂ -C ₃ -alkyl, (pyrrolidino)C ₂ -C ₃ -alkyl and (morpholino)C ₂ -C ₃ -alkyl.

Pharmaceutical composition according to the present invention

In the present invention, "pharmaceutical composition" means a mixture containing certain amounts of specific ingredients or including them in certain ratios.

The pharmaceutical composition proposed in the present invention contains an active ingredient (for example, a compound of formula (I), (II), (III), (I-a), (I-b), (I-c) or (I-d)) and may further contain pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means one or more solid or liquid excipients or encapsulating materials that are suitable for administration to mammals. The term "pharmaceutically acceptable" as used in the present invention means pharmaceutically acceptable in terms of effectiveness, safety, or the like.

Examples of material that can be used as a pharmaceutically acceptable carrier include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as lecithin; dyes; flavoring additives; tableting agents; stabilizers; antioxidants; antiseptics; pyrogen-free water; isotonic solution; and phosphate buffer solutions.

If a pharmaceutical composition according to the present invention is used, examples of administration methods include oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical and topical (drops, powder, ointment, gel or cream) administration and inhalation (oral or nasal sprays). Examples of its dosage forms include tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions placed in containers intended for individual dosage administration. Alternatively, the dosage form may be designed for various administration techniques, including controlled delivery formulations, such as subcutaneous implantation.

These preparations are prepared by well-known techniques using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, modifiers and diluents.

Examples of excipients may include starches such as starch, potato starch and corn starch, lactose, crystalline cellulose and calcium hydrogen phosphate.

Examples of coating agents may include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax and paraffin.

Examples of binders may include polyvinylpyrrolidone, macrogol and the same compounds as those listed as excipients.

Examples of disintegrants may include the same compounds listed as excipients and chemically modified starches and celluloses such as croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone.

Examples of stabilizers may include: p-hydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of modifiers may include commonly used sweeteners, acidulants and flavoring agents.

Liquid preparations can be prepared using a solvent such as ethanol, phenol, chlorocresol, purified water or distilled water.

Examples of surfactants or emulsifiers may include polyoxyl 40 stearate and lauromacrogol.

If the pharmaceutical composition of the present invention is used, the amount of the pharmaceutical drug of the present invention used varies depending on symptoms, age, body weight, relative health status, use of other treatments, administration methods, and the like. In the case of oral agents, a typical effective amount, for example for a patient (warm-blooded animal, especially a human) is preferably 1 to 20 mg/(kg body weight), more preferably 1 to 10 mg/(kg body weight) per day per day. based on the amount of the active ingredient (the compound of the present invention described by formula (I)). The daily dose for an adult patient of normal body weight is preferably in the range of 60 to 1200 mg.

The pharmaceutical composition of the present invention can be used to prevent or treat a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, or to prevent or suppress ectopic calcification.

Chronic kidney disease is classified into stages 1 to 5 based on GFR (glomerular filtration rate): GFR of 90 or more corresponds to stage 1, GFR of 60 or more to less than 90 corresponds to stage 2; A GFR of 30 or more to less than 60 corresponds to stage 3; A GFR of 15 or more to less than 30 corresponds to stage 4; and a GFR of less than 15 corresponds to stage 5 ("Clinical Practice Guidelines for CDK 2012" Japanese Journal of Nephrology, 2012; 54 (8); 1031-1189).

In one embodiment of the present invention, the pharmaceutical composition proposed in the present invention is used for the prevention or treatment of chronic kidney disease in stages 2 to 4 according to the GFR classification.

According to the invention, it has been found that in animal models for hyperphosphatemia and chronic kidney disease, the expression level of NaPi-IIb in the gastrointestinal tract is reduced, but the expression level of PiT-1 and PiT-2 does not change and, as a result, the extent of phosphate uptake by PiT- 1 and PiT-2 in terms of total absorption of phosphate in the gastrointestinal tract becomes relatively large. From these data, according to the invention, it was found that inhibition of PiT-1 or PiT-2 leads to an excellent effect for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, or for preventing or suppressing ectopic calcification. In addition, according to the invention, it has been found that for the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and arteriosclerosis associated with vascular calcification, or for the prevention or suppression of ectopic calcification, the best effect is achieved when inhibited all transporters, NaPi-IIb, PiT-1 and PiT-2, than when only NaPi-IIb was inhibited.

When using the pharmaceutical composition of the present invention, in the case of administering a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, and a phosphorus scavenger for the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic disease kidney and vascular calcification or for preventing or suppressing ectopic calcification, a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 (hereinafter referred to in the present invention as a “transporter inhibitory substance”), and The phosphorus scavenger can be administered simultaneously or separately. The pharmaceutical composition proposed in the present invention can be formulated as a combined drug containing both a transporter inhibitory substance and a phosphorus scavenger. In addition, the drug containing the transporter inhibitory substance and the drug containing the phosphorus scavenger can be prepared separately and used simultaneously or sequentially. In addition, the pharmaceutical composition can be formulated as a kit comprising a drug containing a transporter inhibitory substance and a drug containing a phosphorus scavenger.

In the pharmaceutical composition mentioned above, in the case of using a transporter inhibitory substance and a phosphorus scavenger that are included in different drugs, the dosage forms of the drugs may be the same or different. For example, the drugs may both be parenteral drugs, injectables, drops, and intravenous drugs, but may be in different dosage forms, or the drugs may both be parenteral drugs, injectables, drops, and intravenous drugs, and may be the same dosage forms. In addition, one or more other drugs may be combined in a pharmaceutical composition.

Another object of the present invention is a pharmaceutical composition containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 (hereinafter referred to as a “transporter inhibitory substance”) as an active ingredient, and this composition is used in combination with a phosphorus scavenger to prevent or treat hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and vascular calcification or to prevent or suppress ectopic calcification. If the pharmaceutical composition of the present invention containing a transporter inhibitory substance as an active ingredient is used in combination with a phosphorus scavenger, the composition can be administered simultaneously with the phosphorus scavenger. In addition, the composition can be administered before or after the introduction of the phosphorus scavenger. In the case where the transporter inhibitory substance is administered after administration of the phosphorus scavenger, the timing of administration of the transporter inhibitory substance can be optimized based on the measurement of the residual concentration of the phosphorus scavenger in the subject. This concentration can be determined based on the results of analysis of samples taken from the subject using analytical techniques known to those skilled in the art using various separation techniques such as chromatography.

Another object of the present invention is a pharmaceutical composition that contains a phosphorus scavenger as an active ingredient, and this composition is used in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 (hereinafter referred to in the invention as a "transporter inhibitory substance") for the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and vascular calcification or for the prevention or suppression of ectopic calcification. If a pharmaceutical composition containing a phosphorus scavenger as an active ingredient is used in combination with a transporter inhibitory substance, the composition may be administered simultaneously with the transporter inhibitory substance or may also be administered before or after administration of the transporter inhibitory substance.

In the case where the phosphorus scavenger is administered before administration of the transporter inhibitory substance, the timing of administration of the phosphorus scavenger can be optimized based on the measurement of the residual concentration of the phosphorus scavenger in the subject. This concentration can be determined based on the results of analysis of samples taken from the subject using analytical techniques known to those skilled in the art using various separation techniques such as chromatography.

Substances that inhibit one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2

In the present invention, "a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2" includes any substances (compounds, antibodies, antibody fragments, etc.) that inhibit the absorption of phosphorus in the gastrointestinal tract. -intestinal tract, carried out by one or more sodium-dependent phosphate transporters selected from NaPi-IIb, PiT-1 and PiT-2. The term “a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2” includes “a substance that inhibits one or more transporters selected from PiT-1 and PiT-2”. Examples of "a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2" may include a substance that inhibits NaPi-IIb, a substance that inhibits PiT-1, a substance that inhibits PiT-2 , a substance that inhibits NaPi-IIb and PiT-1, a substance that inhibits NaPi-IIb and PiT-2, a substance that inhibits PiT-1 and PiT-2, and a substance that inhibits NaPi-IIb, PiT-1 and PiT-2.

Specific examples of "low molecular weight compounds that inhibit one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2" may include the compounds of paragraphs (1-1) to (1-49) or salts or solvates of the compounds or salts which are described as components of pharmaceutical compositions. Other specific examples may include the compounds disclosed in WO 2012/006475, WO 2011/136269, WO 2013/062065, WO 2013/082756, WO 2013/082751 and WO 2013/129435, or salts thereof, or solvates of the compounds or salts.

Other specific examples may include the compound represented by the formula selected from the following formulas (1) to (5), or a salt thereof, or a solvate of the compound or a salt.

(Formula 7)

(where Ac denotes an acetyl group)

Of the routes of administration of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, the oral or parenteral route may preferably be used, but the oral route is more preferred. The dosage form for oral administration may be selected, as appropriate, from any of the dosage forms, such as, for example, liquid, powder, granular, tablet, enteric-coated, and capsule. Such dosage form is prepared as a medicinal product according to techniques known to those skilled in the art. For example, the active ingredient is first combined with a suitable pharmacologically acceptable carrier or vehicle, including, but not limited to, sterile water or normal saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, an excipient, diluent, antiseptic or binder and then the combined components are mixed to form a unit dosage form as required by normal acceptable pharmaceutical practice and formulated into a medicinal product by a formulation technique such as freeze-drying or tabletting.

Phosphorus absorber

In the present invention, “phosphorus scavenger” includes any phosphorus scavenger that is known or believed to inhibit the absorption of phosphorus in the gastrointestinal tract by scavenging phosphorus. "Phosphorus scavenger" includes, but is not limited to: metal-free polymeric scavengers, typical examples of which are bixalomer, sevelamer carbonate, and sevelamer hydrochloride; calcium salt preparations, typical examples of which are precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, and keto acid calcium salt; and metal-containing scavengers, typical examples of which are lanthanum carbonate, aluminum hydroxide, iron preparations (iron(III) sucrose oxyhydroxide (polynuclear iron(III) oxide hydroxides), polynuclear iron(III) oxide hydroxide), fermagate (magnesium iron hydroxycarbonate) and citrate hydrate iron(III)).

Of the routes of administration of the phosphorus scavenger used in the present invention, the oral route or the parenteral route may preferably be used, but the oral route is more preferred. The dosage form for oral administration may be selected, as appropriate, from any of the dosage forms, such as, for example, liquid, powder, granular, tablet, enteric-coated, and capsule. The phosphorus scavenger in such dosage form is prepared in the form of a medicinal product according to a method known to specialists in the art. For example, the phosphorus scavenger is first combined with a suitable pharmacologically acceptable carrier or vehicle, including, but not limited to, sterile water or normal saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, an excipient, diluent, antiseptic, or binder, and then the combined components are mixed to form a unit dosage form as required by normal acceptable pharmaceutical practice and formulated into a medicinal product by a formulation technique such as freeze-drying or tabletting.

In the present invention, the combined use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2 (hereinafter referred to as a "transporter inhibitory substance" in the present invention) and a phosphorus scavenger means that the transporter inhibitory the substance and the phosphorus scavenger are administered or applied (hereinafter, the term “administered” is simply used in the present invention) in combination and thus in the order of administration, the time interval between administrations, etc. no restrictions are imposed. In addition, the transporter inhibitory substance and the phosphorus scavenger can be combined and used as a set. In addition, in the case where a transporter inhibitory substance and a phosphorus scavenger are used in combination according to the present invention, the dose of each of the two drugs can optionally be reduced compared to that required when one of them is administered separately.

In the case where the transporter inhibitory substance and the phosphorus scavenger are administered separately, the time interval between the administrations of the transporter inhibitory substance and the phosphorus scavenger is not particularly limited and can be determined by factors such as the route of administration or the dosage form. For example, the time period may be from 0 hours to 168 hours, preferably from 0 hours to 72 hours, more preferably from 0 hours to 24 hours, and even more preferably from 0 hours to 12 hours. Other factors that may also be considered include: as the route of administration or dosage form, but also the residual concentration of each transporter inhibitory substance and phosphorus scavenger in the subject. More preferably, in the case where the phosphorus scavenger is administered before administration of the transporter inhibitory substance, the transporter inhibitory substance can be administered at a time when the determined residual concentration of the phosphorus scavenger in the subject reaches a value at which the desired effect of the phosphorus scavenger can be achieved. This concentration can be determined based on the results of analysis of samples taken from the subject using analytical techniques known to those skilled in the art using various separation techniques such as chromatography.

In contrast, in the case where the transporter inhibitory substance is administered before administration of the phosphorus scavenger, the phosphorus scavenger can be administered at a time when the determined residual concentration of the transporter inhibitory substance in the subject reaches a value at which the desired effect of the phosphorus scavenger can be achieved. This concentration can be determined based on the results of analysis of samples taken from the subject using analytical techniques known to those skilled in the art using various separation techniques such as chromatography.

In the case where the pharmaceutical composition of the present invention is formulated as a combined drug containing both a transporter inhibitory substance and a phosphorus scavenger, no special restrictions are imposed on the content of the transporter inhibitory substance and the phosphorus scavenger. Of the routes of administration of the combined drug, the oral or parenteral route may preferably be used, but the oral route is more preferred. The dosage form for oral administration may be selected, as appropriate, from any of the dosage forms, such as, for example, liquid, powder, granular, tablet, enteric-coated, and capsule. The phosphorus scavenger in such dosage form is prepared in the form of a medicinal product according to a method known to specialists in the art.

Below, the present invention provides general procedures for preparing the compound of formula (I) and examples.

General synthesis procedure

The compound of formula (I) can be synthesized by various methods. Some of these techniques are described with reference to the diagrams below. These schemes are provided for illustrative purposes and the present invention is not limited to the chemical reactions and conditions described. Although certain substituents have been omitted from the diagrams below to facilitate understanding, such exclusion is not intended to limit the disclosure of the diagrams. Exemplary compounds of the present invention can be synthesized using suitable intermediates, compounds known in the art, and reagents. In the formulas of the general synthetic procedures described below, the variable groups designated by R ¹ , R ² , etc., and the variables designated by n, etc., have the same meanings as the values of the variable groups designated using R ¹ , R ² , etc., and variables denoted by n, etc. in compounds described by the general formulas defined in the present invention.

The compound of the present invention can be synthesized according to the methods given below.

Scheme 1 (method A)

Formula 8

in which R ²¹ denotes C ₁ -C ₃ -alkyl; R ²² is C ₁ -C ₅ -alkyl; and R ³ =O (2) denotes an aldehyde or ketone formed by converting the carbon atom at the alkyl bonding position described by R ³ with a carbonyl.

Step 1 involves reacting a compound of formula (1) with an aldehyde or ketone (2) in a suitable solvent such as methanol or dichloromethane to synthesize compound (3). The reaction is carried out at a temperature of, for example, 0° C. to room temperature for, for example, 0.5 hours to 24 hours. The resulting hydrazone derivative (3) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

A number of suitable methods for the synthesis of hydrazine (1) have been described, such as that shown in Scheme 1 (this reaction can be carried out as described, for example, in Synthetic communications, 40, 654-660; 2010, Journal of Heterocyclic Chemistry, 24 (3) , 725-731; 1987, and Synthesis, (6), 423-424; 1979).

Step 2 involves the reduction of hydrazone (3) in the presence of a reducing reagent such as sodium cyanoborohydride or a borane-pyridine complex in a suitable solvent such as methanol or acetic acid to produce hydrazine (4). The reaction is carried out at a temperature of, for example, from 0°C to 50°C, for example, from 0.5 hours to 60 hours. The resulting hydrazine (4) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Step 3 involves the reaction of hydrazine (4) with the partial ester (5) using a condensing reagent such as N,N'-dicyclohexylcarbodiimide (DCC) n-hydrate, 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (GATU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) or cyclic anhydride 1-propanephosphonic acid (T3P), in a suitable solvent such as dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran or ethyl acetate. The reaction is carried out at a temperature of, for example, from 0°C to 50°C, for example, from 0.5 hours to 24 hours. The resulting ester form (6) is isolated according to a general procedure and, if necessary, can be purified using crystallization or chromatography.

The partial ester (5) shown in Scheme 1 can be synthesized from Meldrum acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and alcohol (this reaction can be carried out as described in e.g. Publications Organic Letters, 7 (3), 463-465; 2005).

Step 4 involves cyclization of the ester form (6) using a base such as potassium carbonate, cesium carbonate, sodium methoxide or sodium hydride, in a suitable solvent such as methanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, diethyl ether or tetrahydrofuran. The reaction is carried out at a temperature of, for example, from 0°C to 110°C, for example, from 0.5 hours to 24 hours. The resulting cyclized form (7) is isolated according to a general procedure and, if necessary, can be purified using crystallization or chromatography.

Step 5 involves reacting the cyclized form (7) with various amines (8) in a suitable solvent such as benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. The reaction is carried out at a temperature of, for example, from 50°C to 120°C, for example, from 0.5 hours to 5 hours. The resulting amide form (formula I) is isolated according to a general procedure and, if necessary, can be purified with using crystallization or chromatography.

R ²¹ is preferably methyl and R ²² is preferably methyl or isobutyl.

The compound of formula I can also be synthesized by the reaction between the keto form (9) and an isocyanate as shown in Scheme 2 (Procedure B).

Scheme 2 (method B)

Formula 9

in which R ²² is as defined in Scheme 1.

The keto form (9) as a product in step 1 can be synthesized by decarboxylation of the ester form (7) (this reaction can be carried out as described, for example, in Synthesis, (15), 2487-2491; 2009).

Step 2 involves reacting the keto form (9) with an isocyanate in the presence of a base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran. The reaction is carried out at a temperature of, for example, from 0°C to 50°C, for example, from 0.5 hours to 5 hours. The resulting amide form (formula I) is isolated according to a general procedure and, if necessary, it can be purified with using crystallization or chromatography.

The compound of formula I can also be synthesized by cyclization of the amide form, as shown in Scheme 3 (Method C).

Scheme 3 (method C)

Formula 10

in which R ²¹ is as defined in Scheme 1.

Step 1 involves the reaction of hydrazine (4) with a partial amide (10) in the presence of a condensing reagent such as N,N'-dicyclohexylcarbodiimide (DCC), 4-(4,6-dimethoxy-1,3,5-triazine) n-hydrate -2-yl)-4-methylmorpholinium chloride (DMT-MM), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (GATU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) or cyclic anhydride 1-propanephosphonic acid (T3P), in a suitable solvent such as dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran or ethyl acetate. The reaction is carried out at a temperature of, for example, from 0°C to 50°C, for example, from 0.5 hours to 24 hours. The resulting amide form (11) is isolated according to a general procedure and, if necessary, can be purified using crystallization or chromatography.

The partial amide (10) shown in Scheme 3 can be synthesized from Meldrum's acid and an amine (this reaction can be carried out as described, for example, in Bioorganic & Medicinal Chemistry Letters, 19 (13), 3632-3636; 2009).

Step 2 involves cyclization of the amide form (11) using a base such as sodium methoxide, potassium carbonate, cesium carbonate or sodium hydride in a suitable solvent such as methanol, N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran. The reaction is carried out at a temperature of, for example, from 0° C. to 110° C., for example, from 0.5 hours to 24 hours. The resulting compound of formula I is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

The compound of formula I can also be synthesized by alkylation as shown in Scheme 4 (Method D).

Scheme 4 (method D)

Formula 11

Three typical techniques for stage 1 are given below.

Method 1 involves debenzylation of compound (12) using a palladium catalyst such as palladium(0)-carbon or palladium(II)hydroxide-carbon, or a platinum catalyst such as platinum oxide ( _PtO2 ) in a suitable solvent such as methanol , ethyl acetate, N,N-dimethylformamide or N,N-dimethylacetamide under a hydrogen atmosphere. The reaction is carried out at a temperature of, for example, room temperature to the boiling point of the solvent over a period of, for example, 1 hour to 24 hours. Procedure 2 involves reacting compound (12) in the presence of an oxidizing reagent such as 2,3-dichloro-5 ,6-dicyano-p-benzoquinone or ammonium hexanitratocerate(IV), in a suitable solvent such as dichloromethane or acetonitrile. The reaction is carried out at a temperature of, for example, room temperature to the boiling point of the solvent over a period of, for example, 1 hour to 60 hours. Procedure 3 involves reacting compound (12) in the presence of an organic acid such as trifluoroacetic acid or trifluoromethanesulfonic acid, in a suitable solvent such as dichloromethane or methanol. The reaction is carried out at a temperature of, for example, from 0°C to the boiling point of the solvent for, for example, from 0.5 hours to 5 hours. The resulting NH form (13) is isolated according to a general procedure and, if necessary, can be purified using crystallization or chromatography.

Step 2 involves reacting the NH form (13) with an alkylating reagent such as an alkyl halide or an alkyl sulfonate in the presence of a suitable base such as sodium hydride, potassium tert-butoxide or potassium pentoxide, in a suitable solvent such as N,N-dimethylformamide, N ,N-dimethylacetamide, tetrahydrofuran or dimethyl sulfoxide. The reaction is carried out at a temperature of, for example, from 0° C. to the boiling point of the solvent for, for example, from 0.5 hours to 24 hours. The resulting compound of formula I is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography .

In -OSO ₂ R ²³ shown in this diagram, R ²³ is C ₁ -C ₅ alkyl, optionally substituted with one or more halogen atoms, or aryl, wherein the aryl group is optionally substituted with one or more halogen atoms or alkyl groups. Specific examples of R ²³ include methyl, trifluoromethyl, phenyl and 4-methylphenyl.

The compound of Formula I can also be synthesized by alkylation as shown in Scheme 5 (Procedure E).

Scheme 94 (method E)

Formula 12

in which R ²² is as defined in Scheme 1.

The reaction in step 1 of scheme 5 (method E) can be carried out in the same way as in step 1 of scheme 4 (method D).

The reaction in step 2 of scheme 5 (method E) can be carried out in the same way as in step 2 of scheme 4 (method D). The compound of formula I can be prepared in the same manner as in step 5 of scheme 1 from the resulting ester form (7).

Side chain introduction technique

Scheme 6 (method F)

Formula 13

in which n is an integer ranging from 1 to 10, and R ²⁴ denotes a C ₁ -C ₈ alkoxy group, optionally substituted by one or more R ¹² substituents.

The procedure of Scheme 6 (Procedure F) involves reacting the phenol derivative (16) with an alkylating reagent such as an alkyl halide or alkyl sulfonate in the presence of a suitable base such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide or potassium pentoxide in a suitable solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-acetamide, dimethyl sulfoxide or acetone. The reaction is carried out at a temperature of, for example, 0° C. to the boiling point of the solvent over a period of, for example, from 0.5 hours to 12 hours. The resulting compound described by formula III is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography. The compound obtained in Scheme 6 can, if necessary, be treated to remove various protecting groups and carry out other procedures to synthesize the derivative.

Scheme 7 (method G)

Formula 14

in which n and R ²⁴ are as defined in Scheme 6.

The procedure in Scheme 7 (Method G) involves the reaction of the phenol derivative (16) with various alcohols using a suitable Mitsunobu reagent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N,N',N'-tetraisopropyl azodicarboxamide (TIPA), 1,1'-(azodicarbonyl)dipiperidine (ADDP) or N,N,N',N'-tetramethylazodicarboxamide (TMAD), in the presence of a suitable trivalent organic phosphorus reagent such as triphenylphosphine or tributylphosphine, in a suitable solvent such as dichloromethane, tetrahydrofuran, acetonitrile, toluene, or benzene. The reaction is carried out at a temperature of, for example, 0° C. to the boiling point of the solvent over a period of, for example, from 0.5 hours to 24 hours. The resulting compound, described by formula III, is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography. The compound obtained in Scheme 7 can, if necessary, be treated to remove various protecting groups and carry out other procedures to synthesize the derivative.

Scheme 96 (method N)

Formula 15

in which n is an integer equal to from 1 to 10, and R ²⁵ denotes (C ₁ -C ₄ -alkoxy)carbonyl, C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituent, C ₂ -C ₁₀ -alkynyl, optionally substituted with one or more R ¹¹ substituents, or a C ₁ -C ₄ -alkylthio group, optionally substituted with one or more R ¹³ substituents.

The procedure in Scheme 8 (Procedure H) involves the reaction of a bromobenzene or iodobenzene derivative (17) using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) (Pd( _Ph3P ) ₄ ), tris(dibenzylideneacetone)dipalladium(0) ( Pd ₂ (dba) ₃ ), complex 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)-dichloromethane (PdCl ₂ (dppf)-CH ₂ Cl ₂ ), palladium(II) acetate (Pd(OAc) ₂ ) or dichlorobis(triphenylphosphine)palladium(II) (PdCl ₂ (Ph ₃ P) ₂ ), optionally with the addition of a phosphine ligand such as triphenylphosphine (Ph ₃ P), tri-tert-butylphosphine (tBu ₃ P) or tri-o -tolylphosphine ((o-tol) _3P ), a copper catalyst such as copper(1) iodide, and a suitable base such as sodium carbonate, triethylamine or potassium carbonate, in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N -dimethylformamide, N,N-dimethylacetamide, toluene, benzene, 1,2-dimethoxyethane, 1,4-dioxane, ethanol or acetonitrile, for introducing, for example, sulfur, alkane, alkyne or alkoxycarbonyl. If R ²⁵ is (C ₁ -C ₄ -alkoxy)carbonyl, carbon monoxide and a C ₁ -C ₄ alcohol can be used as reactants in this reaction, for example. If R ²⁵ is C ₁ -C ₁₀ -alkyl, optionally substituted with one or more R ¹⁰ substituents, or C ₂ -C ₁₀ -alkynyl, the reactant in this reaction can be, for example, acetylene or (C ₁ -C ₈ - alkyl)-C≡CH. If R ²⁵ denotes a C ₁ -C ₄ -alkylthio group, optionally substituted by one or more R ¹³ substituents, for example, a C ₁ -C ₄ -alkyl mercaptan can be used as a reactant in this reaction. The reaction is carried out at a temperature of, for example, from 0° C. to the boiling point of the solvent for, for example, from 0.5 hours to 60 hours. The resulting compound, described by formula IV, is isolated according to a general procedure and, if necessary, can be purified using crystallization or chromatography. The compound obtained in Scheme 8 can, if necessary, be treated by hydrogenation of the double bond and triple bond, oxidation or alkylation of the sulfur atom, removal of various protecting groups, and other procedures to synthesize the derivative.

Scheme 9 (method I)

Formula 16

in which R ²² , R ²³ and R ²⁵ are as defined in Schemes 1 and 8.

The reaction of Scheme 9 (Procedure I) can be carried out in the same manner as in Scheme 8 with compound (18) as the starting material. The compound of formula IV can be prepared in the same manner as in step 5 of scheme 1 from the resulting ester form (19).

Scheme 98 (method J)

Formula 17

wherein

Ar ¹ denotes C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl, where this group is optionally substituted with Rb and/or Rc; And

Rd is selected from the group consisting of 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituents, C ₆ -C ₁₀ -aryl, optionally substituted with one or more R ¹⁴ substituents, and 5-10 membered heteroaryl, optionally substituted with one or more substituent R ¹⁴ .

Examples of -B(pin) in the above formula include the following structure:

Formula 18

The methodology of the scheme 10 (method J) includes the reaction of the derivative of the derivative of the arilogenide (20) with arilboronic acid, heteroarillaborne acid, heterocycliclborne acid, ailboronic acid ester, heteroarilarylboronic acid ester, a heterocycliclborne acid ether. fishing, heterocycliclotricylolov, etc. using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) (Pd( _Ph3P ) ₄ ), tris(dibenzylideneacetone)dipalladium(0) ( _Pd2 (dba) ₃ ), 1,1'-bis dichloride complex (diphenylphosphino)ferrocene palladium(II)-dichloromethane (PdCl ₂ (dppf)⋅CH ₂ Cl ₂ ), or palladium(II) acetate (Pd(OAc) ₂ ), optionally with the addition of a phosphine ligand such as triphenylphosphine (Ph ₃ P) , tri-tert-butylphosphine (tBu ₃ P) or tri-o-tolylphosphine ((o-tol) ₃ P), and a suitable base such as sodium carbonate, triethylamine or potassium carbonate, in a suitable solvent such as tetrahydrofuran, acetonitrile , toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane (DME) or 1,4-dioxane under nitrogen to introduce an aryl group. The reaction is carried out at a temperature equal to, for example, from room temperature to the boiling point of the solvent for a period of, for example, from 0.5 hours to 12 hours. The resulting bisaryl form (formula V) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Scheme 11 (method K)

Formula 19

wherein

R ²³ is as defined above;

Ar ¹ and Rd are as defined in Scheme 10; And

R ¹⁴ is selected from the group consisting of a cyano group, a C ₁ -C ₄ alkoxy group optionally substituted with one or more halogen atoms, and -NR ²⁷ R ²⁸ (R ²⁷ and R ²⁸ are each independently selected from the group optionally including (C ₁ -C _3- alkoxy)carbonyl-substituted C ₁ -C ₄ -alkyl).

The procedure of Scheme 11 (Procedure K) involves the reaction of a heteroaryl halide or heteroaryl sulfonic acid ester (21) with a nucleophile such as an amine, nitrile or alcohol, optionally in the presence of a base such as sodium hydride, sodium alkoxide, potassium carbonate, sodium carbonate, triethylamine , diisopropylethylamine or diazabicycloundecene (DBU), in a suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran or dimethyl sulfoxide. The reaction is carried out at a temperature equal to, for example, from room temperature to the boiling point of the solvent over a period of, for example, from 0.5 hours to 24 hours. The resulting bisaryl form (formula VI) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Scheme 12 (method L)

Formula 20

wherein

R ²³ is as defined in Scheme 11;

Rd is 5-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; And

Y is selected from the group consisting of a cyano group, a C ₁ -C ₄ alkoxy group optionally substituted with one or more halogen atoms, and -NR ²⁷ R ²⁸ (R ²⁷ and R ²⁸ are each independently selected from the group consisting of optionally (C ₁ -C ₄ -alkoxy)carbonyl-substituted C ₁ -C ₄ -alkyl).

The procedure of Scheme 12 (Procedure L) involves the reaction of a heteroaryl halide, heteroaryl sulfonic acid ester, or nitroheteroaryl (22) containing an electron-withdrawing substituent (EAA) with a nucleophile such as an amine, nitrile, or alcohol, optionally in the presence of a base such as sodium hydride , sodium alkoxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine or diazabicycloundecene (DBU), in a suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, or an alcohol solvent. The reaction is carried out at a temperature equal to, for example, from room temperature to the boiling point of the solvent over a period of, for example, from 0.5 hours to 24 hours. The resulting bisaryl form (formula VII) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Synthesis of starting materials

Scheme 13 (method M)

Formula 21

in which Ar ¹ and Rd are as defined in Scheme 10.

In accordance with Scheme 13 (Method M), arylamine (8) is synthesized (where Rd denotes a 5-10 membered heterocycloalkyl, optionally substituted with one or more R ¹⁴ substituents, C ₆ -C ₁₀ -aryl, optionally substituted with one or more R ¹⁴ substituents , or 5-10 membered heteroaryl, optionally substituted with one or more R ¹⁴ substituents), intended for use in the reaction in step 5 of scheme 1. This procedure involves reacting an aryl halide (23) or (26) with an arylboronic acid, an arylboronic acid ester, aryltrialkyltin, etc. in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) optionally adding a base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydroxide, in a suitable solvent such as water, toluene, ethanol, N ,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, 1,2-dimethoxyethane or tetrahydrofuran. The reaction is carried out at a temperature equal to, for example, from room temperature to the boiling point of the solvent for, for example, from 0.5 hours to 24 hours. The resulting bisaryl form (25) or (28) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Scheme 102 (method N)

Formula 22

in which R ¹ , R ⁴ , R ⁵ and R ²¹ are as defined above.

Hydrazine is synthesized according to Scheme 14 (Procedure N) for use in reaction step 1 of Scheme 1. Compound (1) can be synthesized as described, for example, in Bioorganic & Medicinal Chemistry Letters 13 (2003) 2413-2418.

Scheme 15 (method O)

Formula 23

wherein R ²⁶ is benzyl, methyl or tert-butyl and R ¹ , R ⁴ and R ⁵ are as defined above.

In accordance with Scheme 15 (Method O), amine (34) is synthesized to synthesize hydrazine (1) for use in the reaction in step 1 of Scheme 1.

Step 1 involves N-alkylation of the carbamate protected amino acid using a suitable alkaline reagent such as sodium hydride, potassium carbonate or cesium carbonate or a silver salt such as silver(I) oxide in the presence of an alkyl halide in a suitable solvent such as N,N -dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran or dimethyl sulfoxide. The reaction is carried out at a temperature of, for example, from 0°C to 80°C, for example, from 0.5 hours to 5 hours. The resulting N-alkyl form (33) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography.

Step 2 involves removing the carbamate protecting group (33), for example in the presence of an acid such as hydrochloric acid or trifluoroacetic acid, or by catalytic reduction with hydrogen in the presence of a catalyst such as palladium. The reaction is carried out at a temperature of, for example, 0°C to 50°C for, for example, 0.5 hours to 24 hours. A solvent is used in the reaction, for example a suitable solvent such as dichloromethane or acetonitrile for acidic conditions or, for example, a solvent such as ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or methanol for hydrogen catalytic reduction. The resulting N-alkyl form (34) is isolated according to a general procedure and, if necessary, can be purified by crystallization or chromatography. Hydrazine (1), shown in Scheme 1, can be synthesized from amine (34), as described, for example, in Synthetic communications, 40, 654-660; 2010, Journal of Heterocyclic Chemistry, 24 (3), 725-731; 1987, and Synthesis, (6), 423-424; 1979.

Scheme 16 (method P)

Formula 24

in which R ¹ , R ⁴ , R ⁵ and R ²⁶ are as defined above.

In accordance with Scheme 16 (Procedure P), the carbamate-protected amino acid (36) is synthesized to synthesize compound (33) for use in the reaction in step 1 of Scheme 15. Compound (36) can be synthesized using the Curtius rearrangement of carboxylic acid (35) ( this reaction can be carried out as described, for example, in J. Org. Chem., 1994, 59 (26), 8215-8219). Compound (33) can be synthesized in the same manner as in step 1 of Scheme 15.

Below, the present invention is described in more detail with reference to comparative examples and examples. However, the present invention is not limited to these examples.

EXAMPLES

The contents of the present invention are further described with reference to the following examples and comparative examples. However, the present invention is not limited to the contents of these examples. All starting materials and reagents were purchased from manufacturers or synthesized according to methods known in the art. Each compound is purified by HPLC (high performance liquid chromatography) using an AutoPurificationHPLC/MS System (manufactured by Waters Corp.). ¹ H-NMR or ¹³ C-NMR spectra were recorded using Me ₄ Si as an internal standard and Agilent 400-MR (manufactured by Agilent Technologies, Inc.) or AVANCE3 Cryo-TCI (Bruker Corp.) (s = singlet, brs = wide singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double doublet doublet, dt = double triplet, td = triple doublet and m = multiplet). Mass spectrometry was performed using an SQD (Waters Corp.), 2020 (Shimadzu Corp.), or 2010EV (Shimadzu Corp.) mass spectrometer. Retention time measurements and liquid chromatography-mass spectrometry (LCMS) mass spectrometry were performed using the following instrumentation and analytical conditions:

A compound containing a C=N bond in the hydrazone structural formula, described by the following formula

Formula 25

used in the next reaction without specifically confirming whether the compound was in cis form or trans form, or a mixture of both.

Example 106

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-4a,5,6,7- tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

(S)-1-[(3-fluorobenzylidene)-amino]-pyrrolidine-2-carboxylic acid methyl ester

Formula 26

L-Proline methyl ester hydrochloride (5.00 g, 30.2 mmol) was suspended in dichloromethane (60.4 ml), p-toluenesulfonic acid monohydrate (6.03 g, 31.7 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was then concentrated under reduced pressure and toluene was added to azeotropically remove water, sodium nitrite (2.19 g, 31.7 mmol) suspended in dichloromethane (60.4 mL) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure, and (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester was obtained as a crude product. The resulting crude product was dissolved in acetic acid (30.2 ml) and water (30.2 ml) was added at 0°C, followed by zinc (19.7 g, 302 mmol) and the mixture was stirred under nitrogen at room temperature for 1 h. Then, at 0°C, sodium bicarbonate, methanol (60.4 ml) and 3-fluorobenzaldehyde (3.20 ml, 30.2 mmol) were added to the reaction mixture and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.68 g, 75%).

LCMS: m/z 251 [M+H] ⁺

HPLC retention time: 0.97 min (assay conditions SQD-AA05)

Second stage

(4aS)-1-[(3-Fluorophenyl)methyl]-4a,5,6,7-tetrahydropyrrolo[1,2-b]pyridazine-2,4-dione

Formula 27

(S)-1-[(3-fluorobenzylidene)-amino]-pyrrolidine-2-carboxylic acid methyl ester (5.68 g, 22.7 mmol) was dissolved in acetic acid (22.7 ml) and methanol (22, 7 ml), sodium cyanoborohydride (5.70 g, 90.8 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 14 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, then the mixture was concentrated under reduced pressure and extracted ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain (S)-1-(3-fluorobenzylamino)-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The resulting crude product was dissolved in tetrahydrofuran (22.7 ml), potassium triphosphate (9.64 g, 45.4 mmol) and chlorocarbonylacetic acid methyl ester (2.67 ml, 45.4 mmol) were added at 0° C. and the mixture was stirred in a nitrogen atmosphere at room temperature for 3 hours. Dichloromethane and 1 N were added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-1-[(3-fluorobenzyl)-(2-methoxycarbonylacetyl)-amino]-pyrrolidine-methyl ester. 2-carboxylic acid as a crude product. The resulting crude product was dissolved in N,N-dimethylformamide (22.7 ml), cesium carbonate (22.2 g, 68.1 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 80°C for 9 hours. 1 n. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2,4a,5 methyl ester. 6,7-hexahydropyrrolo[1,2-b]pyridazine-3-carboxylic acid as a crude product. The resulting crude product was dissolved in acetonitrile (227 ml), water (0.41 ml, 22.7 mmol) was added and the mixture was refluxed for 2 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.01 g, 67%).

LCMS: m/z 263 [M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-AA05)

Third stage

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-4a,5,6,7- tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 28

(4aS)-1-[(3-Fluorophenyl)methyl]-4a,5,6,7-tetrahydropyrrolo[1,2-b]pyridazine-2,4-dione (1.50 g, 5.72 mmol) was dissolved in N,N-dimethylformamide (4.00 ml) and then 3-isocyanato-5-methyl-2-trifluoromethylfuran (1.20 g, 6.29 mmol) and sodium hydride (50 wt.% dispersion in mineral oil, 0 .33 g, 6.86 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 90 minutes. 1 N was added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.62 g, 63%).

LCMS: m/z 454 [M+H] ⁺

HPLC retention time: 1.10 min (assay conditions SQD-AA05)

Example 2

(4aR)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-4a,5,6,7- tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from D-proline methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 110

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-6,6-dimethyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5, 7-dihydro-4aH-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

(S)-4,4-Dimethylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride

Formula 29

A solution of hydrogen chloride in 1,4-dioxane (4 M, 5.00 ml) was added to 1-tert-butyl ether, (S)-4,4-dimethylpyrrolidine-1,2-dicarboxylic acid 2-ethyl ester (500 mg , 1.84 mmol) and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting (S)-4,4-dimethylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 4

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-7,7-dimethyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5, 6-dihydro-4aH-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

(S)-5,5-Dimethylpyrrolidine-2-carboxylic acid methyl ester hydrochloride

Formula 30

(S)-5,5-Dimethylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 2.06 mmol) was dissolved in N,N-dimethylformamide (2.06 ml) and then cesium carbonate was added ( 1.00 g, 3.08 mmol) and iodomethane (0.154 ml, 2.47 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. 1 N was added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-tert-butyl ether, 2-methyl ester (S)-5,5-dimethylpyrrolidine-1,2- dicarboxylic acid as a crude product. A solution of hydrogen chloride in 1,4-dioxane (4 M, 5.00 ml) was added to the resulting crude product and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and toluene was added to azeotrope and the title compound was obtained as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting (S)-5,5-dimethylpyrrolidine-2-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 113

(4aS)-1-[(2,3-Difluorophenyl)methyl]-6,6-difluoro-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo- 5,7-dihydro-4aH-pyrrolo[1,2-b]pyridazine-3-carboxamide

2-Methyl-1-tert-butyl diester (S)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid was used as a starting material, 2,3-difluorobenzaldehyde was used as a reagent, and operations similar to those used in Example 3 were carried out to synthesize the compounds described in the table below.

Example 114

(4aR)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-4a-methyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-6,7- Dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

(R)-2-Methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride

Formula 31

(R)-2-Methylpyrrolidine-2-carboxylic acid (300 mg, 2.32 mmol) was dissolved in dioxane (1.20 ml) and water (0.60 ml) followed by sodium hydroxide (139 mg, 3.48 mmol ) and di-tert-butyl dicarbonate (608 mg, 2.79 mmol) were added at 0°C and the mixture was stirred at room temperature for 2 hours. 1N was added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product. Using a procedure similar to that used in the first step of Example 4, the title compound was obtained from the resulting (R)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 7

(4aR)-1-[(2,3-Difluorophenyl)methyl]-4-hydroxy-4a-methyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-6, 7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride obtained in the first step of Example 6 and 2,3 -difluorobenzaldehyde.

Example 8

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-4a-methyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-6,7- Dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

(S)-2-Methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride

Formula 32

Using a procedure similar to that used in the first step of Example 6, the title compound was obtained from (S)-2-methylpyrrolidine-2-carboxylic acid as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (S)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride obtained in the first step and 3-fluorobenzaldehyde.

Example 9

(4aR)-4a-Ethyl-1-[(3-fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-6,7- Dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

By performing operations similar to those used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (S)-2-ethylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 10

(4aR)-1-[(2,3-Difluorophenyl)methyl]-4a-ethyl-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-6, 7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

By performing operations similar to those used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (R)-2-ethylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 2,3-difluorobenzaldehyde.

Example 11

(4aR)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-4a-propyl-6,7- Dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

By performing operations similar to those used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (R)-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 12

(4aR)-1-[(2,3-Difluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-4a-propyl-6, 7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

By performing operations similar to those used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (R)-2-propylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 2,3-difluorobenzaldehyde.

Example 13

6-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

First stage

2,3-Difluoro-1-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzene

Formula 33

2,3-Difluoro-1-[2-chloroethoxy]benzene (4.20 g, 22.0 mmol) was dissolved in N,N-dimethylformamide (32.9 ml), N-(2-methoxyethyl)-N-methylamine (4.35 g, 48.8 mmol) at 25° C., potassium iodide (6.08 g, 36.6 mmol) and potassium triphosphate (7.77 g, 36.6 mmol) were added and the mixture was stirred under nitrogen at 100°C for 2 hours. The reaction mixture was then cooled to 25°C, water (47.0 ml) was added and the resulting mixture was extracted with isopropyl acetate (47.0 ml). 1 n. Hydrochloric acid (47.0 ml) was added to the organic layer for extraction, 5 N. an aqueous sodium hydroxide solution (14.1 ml) was added to the resulting aqueous solution to make it alkaline, and the mixture was extracted with isopropyl acetate (47.0 ml). The organic layer was concentrated under reduced pressure to obtain the title compound (5.15 g, 95%).

¹ H-NMR (DMSO-D ₆ ) δ: 7.16-7.10 (1H, m), 7.06-7.03 (1H, m), 6.99-6.96 (1H, m) , 4.15 (2H, t, J=5.7 Hz), 3.41 (2H, t, J=6.0 Hz), 3.22 (3H, s), 2.78 (2H, t, J=6.0 Hz), 2.59 (2H, t, J=6.0 Hz), 2.28 (3H, s).

Second stage

2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde

Formula 34

N,N-Diisopropylamine (5.92 ml) was dissolved in tetrahydrofuran (62.6 ml) and a solution of n-butyllithium in hexane (1.6 M, 26.2 ml, 41.9 mmol) was added dropwise at -20°C ). After stirring the mixture at -20°C for 30 minutes, it was cooled to -50°C and a solution of 2,3-difluoro-1-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzene (5, 15 g, 21.0 mmol) in tetrahydrofuran (21.0 ml). After stirring the mixture at -40°C for 2 hours, N,N-dimethylformamide (4.94 ml) was added and the mixture was stirred for 30 minutes. The reaction mixture was then heated at -15°C, and a solution of acetic acid (7.31 ml) in water (26.1 ml) and toluene (15.7 ml) was added for liquid-liquid extraction. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane/triethylamine) to give the title compound (2.90 g, 50%).

¹ H-NMR (DMSO-D ₆ ) δ: 10.04 (1H, s), 7.69-7.64 (1H, m), 7.27-7.24 (1H, m), 4.28 (2H, t, J=5.7 Hz), 3.41 (2H, t, J=6.0 Hz), 3.22 (3H, s), 2.81 (2H, t, J=5, 7 Hz), 2.60 (2H, t, J=6.0 Hz), 2.28 (3H, s).

Third stage

Methyl 1-[[(E)-2,3-difluoro-4-[2-[2-[methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate

Formula 35

Methyl 1-(methylamino)cyclobutanecarboxylate-p-toluenesulfonate (1.75 g, 5.54 mmol) (see Comparative Example 86) was dissolved in acetic acid (1.60 ml, 27.7 mmol) and water (9, 0 ml), a solution of sodium nitrite (0.45 g, 6.59 mmol) in water (1.00 ml) was added at 25°C and the mixture was stirred under nitrogen atmosphere for 30 minutes. Ethyl acetate (3.50 ml) and sodium chloride (1.00 g) were added to the reaction mixture, and the organic layer after liquid-liquid extraction was washed with a 15% aqueous solution of dipotassium hydrogen phosphate. Methanol (10.0 ml) was added to the organic layer after washing and 12 N. hydrochloric acid (3.60 ml) was added at -10°C. Zinc dust (0.73 g, 11.1 mmol) was added to the reaction mixture at -30°C and the mixture was stirred for 1 hour. A 28% aqueous solution (3.66 ml) was added to the reaction mixture; a solution of 2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde (1.00 g, 3.66 mmol) in ethyl acetate (2.75 ml) and the mixture was stirred for 30 min . The reaction mixture was then concentrated, ethyl acetate and 15% aqueous potassium dihydrogen phosphate were added for liquid-liquid extraction, and then the organic layer was washed with 15% aqueous sodium hydrogen sulfite and 15% aqueous dipotassium hydrogen phosphate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (1.07 g, 70%).

LCMS: m/z 414[M+H] ⁺

HPLC retention time: 0.65 min (SQD-TFA05)

Fourth stage

Methyl-1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl] methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoyl]amino]-methylamino]cyclobutan-1-carboxylate

Formula 36

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylidenamino]-methylamino]cyclobutane-1-carboxylate (1.00 g , 2.42 mmol) was dissolved in ethyl acetate (8.1 ml), methanesulfonic acid (1.18 ml, 18.1 mmol) was added at 0° C. and the mixture was stirred under nitrogen for 10 min. 5-ethyl-2-methylpyridineborane (0.72 mL, 4.84 mmol) was added to the reaction mixture at 0° C. and the mixture was stirred under nitrogen atmosphere for 30 min. Methanol (0.81 ml) was then added to the reaction mixture at 0°C, 5 M aqueous sodium hydroxide (2.44 ml) was added, and the mixture was stirred at 0°C for 1 hour. A 25% aqueous solution was added to the reaction mixture potassium triphosphate for liquid-liquid extraction. The organic layer was washed with 15% sodium chloride aqueous solution and the filtrate was concentrated under reduced pressure to give methyl 1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylamino] -methylamino]cyclobutane-1-carboxylate as a crude product.

Resulting crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (Comparative Example 82) (1.05 g, 2.66 mmol) dissolved in ethyl acetate (8.00 ml) and N,N-dimethylformamide (4.00 ml), pyridine (1.00 ml) and 2,4,6-tripropyl-1,3,5 were added at -10°C, 2,4,6-trioxatriphosphinane-2,4,6-trioxide (1.7 M solution in ethyl acetate, 2.85 ml, 4.84 mmol) and the mixture was stirred under nitrogen atmosphere for 30 minutes. A 10% sodium chloride aqueous solution was added to the reaction mixture for liquid-liquid extraction. The organic layer was washed with a 15% aqueous dipotassium hydrogen phosphate solution, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.90 g, 97%).

LCMS: m/z 791[M+H] ⁺

HPLC retention time: 0.81 min (SQD-TFA05)

Fifth stage

6-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)- 2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 37

Methyl-1-[[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl-[3-oxo-3[4-(trifluoromethyl)-2-[6 -(trifluoromethyl)pyrimidin-4-yl]anilino]propanoyl]amino]-methylamino]cyclobutane-1-carboxylate (2.06 g, 2.60 mmol) was suspended in isopropanol (28.8 ml), potassium carbonate (718) was added mg, 5.20 mmol) and the mixture was stirred under nitrogen at 50°C for 8 hours. The reaction mixture was then concentrated, 1 M hydrochloric acid (2.60 ml, 2.60 mmol) was added and the resulting mixture was extracted with ethyl acetate. Then the organic layer was washed with 10% aqueous potassium dihydrogen phosphate and 10% aqueous sodium chloride, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.72 g, 87%).

Although tautomers of the compound of interest exist, isomers may be observed in some cases but not others depending on the type of solvent used for the measurement. For example, ¹ H-NMR and ¹³ C-NMR of basic tautometers (chloroform-D) are as follows.

LCMS: m/z 759[M+H] ⁺

HPLC retention time: 0.91 min (SQD-TFA05)

¹ H-NMR (CDCl ₃ ) δ: 16.57 (1H, s), 12.81 (1H, s), 9.61 (1H, s), 8.50 (1H, d, J=8.7 Hz), 7.95 (1H, s), 7.90 (1H, d, J=1.6 Hz), 7.80 (1H, dd, J=8.7, 1.6 Hz), 7, 01 (1H, ddd, J=9.1, 7.2, 1.8 Hz), 6.72 (1H, ddd, J=8.7, 7.2, 1.3 Hz), 5.08- 5.03 (1H, m), 4.19-4.16 (1H, m), 4.19-4.16 (1H, m), 3.54-3.51 (2H, m), 3, 37 (3H, s), 2.93 (2H, brs), 2.73 (2H, brs), 2.56 (1H, m), 2.43 (3H, brs), 2.41 (3H, s ), 1.86 (1H, m), 1.84 (1H, m), 1.82 (1H, m), 1.71 (1H, m), 1.58 (1H, m).

¹³ C-NMR (CDCl ₃ ) δ: 186.1 (qC), 169.8 (qC), 165.7 (qC), 162.8 (qC), 159.3 (CH), 156.6 (qC , q, J _CF =36.3 Hz), 150.4 (qC, dd, J _CF =248.4, 10.5 Hz), 147.9 (qC), 141.1 (qC, dd, J _CF =248.0, 15.0 Hz), 138.8 (qC), 128.3 (CH, q, J _CF =3.3 Hz), 127.8 (qC), 127.1 (CH), 126 .9 (qC, q, J _CF =33.6 Hz), 125.1 (CH), 124.7 (CH), 123.6 (qC, q, J _CF =271.8 Hz), 120.5 (qC, q, J _CF =275.4 Hz), 117.9 (qC, d, J _CF =11.8 Hz), 115.9 (CH), 109.2 (CH, s), 92.3 (qC), 70.5 (CH ₂ ), 68.1 (CH ₂ ), 64.1 (qC), 58.9 (CH ₃ ), 57.4 (CH ₂ ), 56.3 (CH ₂ ) , 43.4 (CH ₃ ), 41.5 (CH ₂ ), 35.0 (CH ₃ ), 32.4 (CH ₂ ), 24.4 (CH ₂ ), 13.4 (CH ₂ ).

Example 14

7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

First stage

Methyl 1-[[(E)-2,3-[difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate

Formula 38

Methyl 1-(methylamino)cyclopentanecarboxylate-p-toluenesulfonate (3.60 g, 10.9 mmol) (see Comparative Example 88) was dissolved in acetic acid (3.10 ml, 54.2 mmol) and water (18, 0 ml), a solution of sodium nitrite (0.91 g, 13.2 mmol) in water (2.00 ml) was added at 25°C and the mixture was stirred under nitrogen atmosphere for 30 minutes. Ethyl acetate (7.00 ml) and sodium chloride (2.00 g) were added to the reaction mixture, and the organic layer after liquid-liquid extraction was washed with a 15% aqueous solution of dipotassium hydrogen phosphate. Methanol (20.0 ml) was added to the organic layer after washing and 12 i was added at -10°C. hydrochloric acid (7.30 ml). Zinc dust (1.44 g, 22.0 mmol) was added to the reaction mixture at -30°C and the mixture was stirred for 1 hour. A 28% aqueous solution (7.30 ml) was added to the reaction mixture; a solution of 2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde (2.00 g, 7.30 mmol) (second step of Example 13) in ethyl acetate (5.40 ml) and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated, ethyl acetate and 15% aqueous potassium dihydrogen phosphate were added for liquid-liquid extraction, and then the organic layer was washed with 15% aqueous sodium hydrogen sulfite and 15% aqueous dipotassium hydrogen phosphate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (2.82 g, 90%).

LCMS: m/z 428[M+H] ⁺

HPLC retention time: 0.61 min (SQD-FA05)

Second stage

Methyl-1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoyl]amino]methylamino]cyclopentane-1-carboxylate

Formula 39

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate (1.00 g , 2.34 mmol) was dissolved in ethyl acetate (10.0 ml), methanesulfonic acid (1.14 ml, 17.6 mmol) was added at 0° C. and the mixture was stirred under nitrogen for 10 min. 5-ethyl-2-methylpyridineborane (0.70 mL, 4.70 mmol) was added to the reaction mixture at 0° C., and the mixture was stirred under nitrogen atmosphere for 30 minutes. Then, methanol (1.00 mL) was added to the reaction mixture at 0°C, 5 M sodium hydroxide aqueous solution (3.00 mL) was added, and the mixture was stirred at 0°C for 1 hour. To the reaction mixture for liquid-liquid extraction a 25% aqueous solution of potassium triphosphate was added. The organic layer was washed with 15% sodium chloride aqueous solution and the filtrate was concentrated under reduced pressure to give methyl 1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylamino] -methylamino]cyclopentane-1-carboxylate as a crude product.

The resulting crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (1.00 g, 2.54 mmol) were dissolved in ethyl acetate (8 .00 ml) and N,N-dimethylformamide (4.00 ml) and then pyridine (1.00 ml) and 2,4,6-tripropyl-1,3,5,2,4 were added at -10°C. 6-trioxatriphosphinane-2,4,6-trioxide (1.7 M solution in ethyl acetate, 2.75 ml, 4.68 mmol) and the mixture was stirred under nitrogen for 30 minutes. A 10% aqueous sodium chloride solution was added to the liquid-liquid extraction reaction mixture. The organic layer was washed with a 15% aqueous dipotassium hydrogen phosphate solution, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.82 g, 97%).

LCMS: m/z 805[M+H] ⁺

HPLC retention time: 0.74 min (SQD-FA05)

Third stage

7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 40

Methyl-1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoyl]amino]-methylamino]cyclopentane-1-carboxylate (500 mg, 0.62 mmol) was suspended in isopropanol (7.00 ml), potassium carbonate (175 mg) was added , 1.27 mmol) and the mixture was stirred under a nitrogen atmosphere at 60°C for 8 hours. The reaction mixture was then concentrated, 1 M hydrochloric acid (1.24 ml, 1.24 mmol) was added and the mixture was extracted with ethyl acetate. Then the organic layer was washed with 10% aqueous potassium dihydrogen phosphate and 10% aqueous sodium chloride, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (432 mg, 90%).

Although tautomers of the compound of interest exist, isomers may be observed in some cases but not others depending on the type of solvent used for the measurement. For example, ¹ H-NMR and ¹³ C-NMR of basic tautometers (chloroform-D) are as follows.

LCMS: m/z 773[M+H] ⁺

HPLC retention time: 0.95 min (SQD-FA05)

¹ H-NMR (CDCl ₃ ) δ: 16.55 (1H, s), 12.83 (1H, s), 9.62 (1H, s), 8.49 (1H, d, J=8.7 Hz), 7.96 (1H, d, J=1.2 Hz), 7.90 (1H, d, J=1.6 Hz), 7.79 (1H, dd, J=8.7, 2 ,0 Hz), 7.04 (1H, dd, J=7.4, 7.4 Hz), 6.73 (1H, dd, J=7.4, 7.4 Hz), 5.05 (1H , d, J=14.2 Hz), 4.19-4.18 (1H, m), 4.19 (2H, brs), 3.55 (2H, brs), 3.37 (3H, s) , 2.96 (2H, s), 2.76 (2H, s), 2.48 (3H, s), 2.45 (3H, s), 2.15 (1H, m), 1.74 ( 2H, m), 1.57 (1H, m), 1.50 (1H, m), 1.45 (2H, m), 1.30 (1H, m).

¹³ C-NMR (CDCl ₃ ) δ: 187.8 (qC), 169.9 (qC), 165.7 (qC), 163.1 (qC), 159.3 (CH), 156.6 (qC , q, J=36.3 Hz), 150.4 (qC, dd, J _CF =248.6, 10.6 Hz), 147.9 (qC), 141.1 (qC, dd, J _CF = 248.3, 14.7 Hz), 138.8 (qC), 128.3 (CH), 127.8 (qC), 127.1 (CH), 126.9 (qC, q, J _CF =33 .4 Hz), 125.5 (CH), 124.7 (CH), 123.6 (qC, q, J _CF = 272.1 Hz), 120.5 (qC, q, J _CF = 275.4 Hz), 117.6 (qC, q, J _CF =12.7 Hz), 116.0 (CH), 109.3 (CH), 93.1 (qC), 71.4 (qC), 70, 4 (CH ₂ ), 68.0 (CH ₂ ), 58.9 (CH ₃ ), 57.3 (CH ₂ ), 56.3 (CH ₂ ), 43.3 (CH ₃ ), 41.6 ( CH ₂ ), 37.6 (CH ₂ ), 36.8 (CH ₃ ), 31.4 (CH ₂ ), 24.8 (CH ₂ ), 23.3 (CH ₂ ).

Example 15

(4aR)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5,6,7,8- tetrahydro-4aH-pyrido[1,2-b]pyridazine-3-carboxamide

First stage

(R)-Piperidine-2-carboxylic acid methyl ester hydrochloride

Formula 41

(R)-Piperidine-2-carboxylic acid (300 mg, 2.32 mmol) was dissolved in methanol (4.64 ml), thionyl chloride (0.508 ml, 6.97 mmol) was added dropwise at 0°C and the mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting (R)-piperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 16

(4aS)-1-[(3-Fluorophenyl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5,6,7,8- tetrahydro-4aH-pyrido[1,2-b]pyridazine-3-carboxamide

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (S)-piperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 17

(4aS)-1-[(5,6-Difluoro-1H-indol-7-yl)methyl]-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2- oxo-5,6,7,8-tetrahydro-4aH-pyrido[1,2-b]pyridazine-3-carboxamide

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from (S)-piperidine-2-carboxylic acid methyl ester hydrochloride and 5,6-difluoro-1H-indole-7-carbaldehyde .

Example 18

1-[(3-Fluorophenyl)methyl]-4-hydroxy-4a-methyl-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5,6,7,8- tetrahydropyrido[1,2-b]pyridazine-3-carboxamide

First stage

2-Methylpiperidine-2-carboxylic acid methyl ester hydrochloride

Formula 42

Using a procedure similar to that used in the first step of Example 4, the title compound was obtained from 2-methylpiperidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting 2-methylpiperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Example 19

1-[2,3-(Difluorophenyl)methyl]-4a-ethyl-4-hydroxy-N-[5-methyl-2-(trifluoromethyl)furan-3-yl]-2-oxo-5,6,7, 8-tetrahydropyrido[1,2-b]pyridazine-3-carboxamide

First stage

2-Ethylpiperidine-2-carboxylic acid methyl ester hydrochloride

Formula 43

Using a procedure similar to that used in the first step of Example 6, the title compound was obtained from 2-ethylpiperidine-2-carboxylic acid hydrochloride as a crude product.

Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting 2-ethylpiperidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluorobenzaldehyde.

Example 20

(4aS,5S,8R)-1-(3-Fluorobenzyl)-4-hydroxy-N-(5-methyl-2-(trifluoromethyl)furan-3-yl)-2-oxo-2,4a,5,6 ,7,8-hexahydro-1H-5,8-methanopyrido[1,2-b]pyridazine-3-carboxamide

First stage

(1S,3S,6R)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester hydrochloride

Formula 44

(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-Butyl ester (500 mg, 2.07 mmol) was dissolved in N,N-dimethylformamide (2.07 ml), cesium carbonate (1.01 g, 3.11 mmol) and iodomethane (0.155 ml, 2.49 mmol) were added and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. 1 N was added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate, 10% aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-tert-butyl ether, 3-methyl ether (1R,3S,4S) -2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid as a crude product. A solution of hydrogen chloride in 1,4-dioxane (4 M, 5.00 mL) was added to the resulting crude product and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and toluene was added to azeotrope and the title compound was obtained as a crude product. Second stage

Using a procedure similar to that used in the first to third steps of Example 1, the compounds described in the table below were synthesized from the resulting (1S,3S,6R)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester hydrochloride and 3-fluorobenzaldehyde.

Comparative Example 1-1

2-Methylpropyl ether (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine -3-carboxylic acid

Formula 45

First stage

Formula 46

(R)-1-((2,3-(difluorobenzylidene)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester (1.31 g, 4.63 mmol) was dissolved in methanol (4.6 ml) and acetic acid acid (4.6 ml), sodium cyanoborohydride (1.19 g, 18.98 mmol) was added and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain the crude product (1.34 g, 102%) (R)-1-((2,3-(difluorobenzyl)amino)-2-methylpyrrolidine-methyl ester 2-carboxylic acid.

Second stage

Formula 47

(R)-1-((2,3-(difluorobenzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester (3.24 g, 11.39 mmol) and 3-butyloxy-3-propionic acid (2 .19 g, 13.67 mmol) was dissolved in dichloromethane (17.7 ml) and then bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (6.9 g, 14.81 mmol) and triethylamine (6.37 ml, 45 .6 mmol) and the mixture was stirred at room temperature for 30 minutes. Dichloromethane and 1N hydrochloric acid were added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified with using silica gel column chromatography (hexane/ethyl acetate) to obtain (R)-1-(N-(2,3-difluorobenzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester (4 .58 g, 94%).

LCMS: m/z 427[M+H] ⁺

HPLC retention time: 1.33 min (assay conditions SMD-TFA05)

Third stage

(R)-1-(N-(2,3-Difluorobenzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester (30.4 g, 71.2 mmol) was dissolved in N ,N-dimethylformamide (142 ml), cesium carbonate (69.6 g, 214 mmol) was added and the mixture was stirred at 80°C for 1 hour. The mixture was then left to cool, it was concentrated under reduced pressure, 2N was added. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-80% ethyl acetate/hexane) to give the title compound (25.33 g, 90%).

LCMS: m/z 395[M+H] ⁺

HPLC retention time: 1.05 min (assay conditions SQD-FA05)

Comparative example 1-2

Methyl (4aR)-4-hydroxy-4a-methyl-2-oxo-1-pentyl-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate

Formula 48

N-pentylaldehyde (0.959 g, 11.1 mmol) was used as a reagent and operations similar to those used in the first step of Comparative Example 1-1 were performed to obtain (R)-1-(pentylamino)-2-methylpyrrolidine-methyl ester. 2-carboxylic acid (1.73 g) as crude product. The resulting hydrazone derivative was dissolved in tetrahydrofuran (14 ml), potassium triphosphate (6.41 g, 30.2 mmol) and methyl 3-chloro-3-oxopropanoate (1.62 ml, 15.1 mmol) were added and the mixture was stirred at room temperature overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and then the organic layer was washed with 1 N. hydrochloric acid, water and brine, it was dried over magnesium sulfate. The resulting mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-1-(3-methoxy-3-oxo-N-pentylpropanamide)-2-methyl ester. Methylpyrrolidine-2-carboxylic acid (1.84 g, 84%) as a yellow oil. The resulting amide (1.84 g, 5.59 mmol) was dissolved in N,N-dimethylformamide (25 ml), cesium carbonate (5.47 g, 16.8 mmol) was added and the mixture was stirred at 80°C for 2 hours The reaction mixture was then cooled to room temperature, ethyl acetate (50 ml) was added and then the organic layer was washed with 1 N. hydrochloric acid, water and brine, it was dried over magnesium sulfate. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.84 g).

LCMS: m/z 297[M+H] ⁺

HPLC retention time: 1.22 min (assay conditions SMD-TFA05)

Comparative example 2

(R)-2,5,5-trimethylpyrrolidine-2-carboxylic acid methyl ester

Formula 49

First stage

Formula 50

4-Chlorobenzaldehyde (0.736 g, 5.23 mmol) was added to a suspension of 2-aminopropanoate tert-butyl ether (0.80 g, 5.51 mmol) and magnesium sulfate (0.66 g, 5.51 mmol) in dichloromethane ( 7.3 ml) and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-((4-chlorobenzylidene)amino)propanoate tert-butyl ester (1.29 g) as a crude product.

Second stage

Formula 51

2-((4-chlorobenzylidene)amino)propanoate tert-butyl ester (2.18 g, 12.2 mmol) obtained in the first step and (S)-4,4-dibutyl-2,6-bis(3 ,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[7,6,1,2-cde]azepinium bromide (91 mg, 0.122 mmol) was dissolved in toluene (85 ml) and 1 -bromo-3-methyl-2-butene (1.71 ml, 14.61 mmol) and cesium hydroxide (9.13 g, 60.9 mmol). After stirring the reaction mixture at 0°C for 4 hours, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure to obtain (R)-2-((4-chlorobenzylidene)amino)-2,5-dimethylhex-4-enoic acid tert-butyl ester as a crude product.

Third stage

Formula 52

1 n. Hydrochloric acid (97 ml, 97 mmol) was slowly added to a solution of (R)-2-((4-chlorobenzylidene)amino)-2,5-dimethylhex-4-enoic acid tert-butyl ester (4.09 g, 12. 2 mmol) obtained in the second stage, in diethyl ether (97 ml). The reaction mixture was stirred vigorously at room temperature for 4 hours. The organic layer was separated and the aqueous layer was washed with diethyl ether. The aqueous layer was then adjusted to pH 9 and extracted with dichloromethane. The extracts were combined, dried and filtered, and the filtrate was concentrated under reduced pressure to give (R)-2-amino-2,5-dimethylhex-4-enoic acid tert-butyl ester as a crude product.

Fourth stage

Formula 53

(R)-2-Amino-2,5-dimethylhex-4-enoic acid tert-butyl ester (1.03 g, 4.83 mmol) obtained in the third step was dissolved in dichloromethane (9.7 ml), added p-toluenesulfonyl chloride (1.11 g, 5.79 mmol), triethylamine (0.81 ml, 5.79 mmol) and 4-dimethylaminopyridine (5.90 mg, 0.048 mmol) and the mixture was stirred at room temperature overnight. Dichloromethane and 1 N were added to the reaction mixture. hydrochloric acid and the mixture was extracted with dichloromethane. The extracts were combined, washed with brine, dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-2,5-dimethyl-2-(4-methylphenylsulfonamide)hex-4-enoic acid tert-butyl ester (1.47 g, 83% ) as a yellow oil.

LCMS: m/z 368[M+H] ⁺

HPLC retention time: 1.40 min (assay conditions SMD-TFA05)

Fifth stage

Formula 54

Tert-Butyl ester (R)-2,5-dimethyl-2-(4-methylphenylsulfonamide)hex-4-enoic acid (1.47 g, 4.00 mmol) obtained in the fourth step was dissolved in chloroform (16, 0 ml) and the solution was cooled to 0°C. Trifluoromethanesulfonic acid (0.14 mL, 1.60 mmol) was added at 0°C and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted dichloromethane. The extracts were combined, washed with brine and dried over sodium sulfate. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid as a crude product.

Sixth stage

Formula 55

Iodomethane (2.99 ml, 4.80 mmol) was added to the suspension of (R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid (1.25 g, 4.00 mmol) obtained in the fourth stage, and potassium carbonate (829 mg, 6.00 mmol) in N,N-dimethylformamide (16.0 ml). The reaction mixture was stirred at room temperature for 1 hour. 1 N was added. hydrochloric acid and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine and dried over sodium sulfate. The resulting mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid methyl ester (1 .24 g, 3.81 mmol) as a pale yellow solid.

LCMS: m/z 326[M+H] ⁺

HPLC retention time: 1.20 min (assay conditions SMD-TFA05)

Seventh stage

(R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid methyl ester (1.24 g, 3.81 mmol) obtained in the sixth step was dissolved in methanol (38.1 ml) and added magnesium (1.85 g, 76 mmol). The reaction mixture was stirred at room temperature for 28 hours. 1 N was added. hydrochloric acid and the aqueous layer were washed with dichloromethane. The pH of the aqueous layer was adjusted to 9 and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (611 mg, 3.57 mmol) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 3.73 (3H, s), 2.36-2.30 (1H, m), 1.88-1.80 (1H, m), 1.69-1 .53 (2H, m), 1.39 (3H, s), 1.18 (3H, s), 1.17 (3H, s).

Comparative example 3

2,3-Difluoro-4-(2-morpholinoethoxy)benzaldehyde

Formula 56

First stage

Formula 57

4-(2-Chloroethyl)morpholine hydrochloride (4.72 g, 25.4 mmol), cesium carbonate (18.8 g, 57.7 mmol) and tetrabutylammonium iodide (0.511 g, 1.38 mmol) were added to the 2.3 solution -difluorophenol (3.00 g, 23.1 mmol) in acetonitrile (46.1 ml) and the mixture was stirred at 65°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure . The residue was dissolved in ethyl acetate, washed with water, 2 N. aqueous sodium hydroxide solution, water and brine, and the organic layer was dried over sodium sulfate. The resulting mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-(2-(2,3-difluorophenoxy)ethyl)morpholine (5.60 g, 99%) in the form of a colorless oil.

LCMS: m/z 244[M+H] ⁺

HPLC retention time: 0.68 min (assay conditions SMD-TFA05)

Second stage

A solution of 4-(2-(2,3-difluorophenoxy)ethyl)morpholine (1.00 g, 4.11 mmol) and N,N,N',N'-tetramethylethylenediamine (0.62 ml, 4.11 mmol) in tetrahydrofuran (13.7 ml) was cooled to -78°C and n-butyllithium (2.14 ml, 5.34 mmol) was added. After stirring the mixture at -78°C for 1 hour, N,N-dimethylformamide (0.35 ml, 4.52 mmol) was added at -78°C. The reaction mixture was slowly heated to -10°C and the reaction was stopped with a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate and the extracts were combined and washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to give the title compound (758 mg, 68%) as a yellow oil.

LCMS: m/z 272[M+H] ⁺

HPLC retention time: 0.62 min (assay conditions SMD-TFA05)

Comparative example 4

2-Methylpropyl ether (4aR)-1-[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-6,7- Dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid

Formula 58

First stage

Formula 59

We used 2,3-difluoro-4-(2-morpholinoethoxy)benzaldehyde and methyl-(R)-2-methylpyrrolidine-2-carboxylic acid hydrochloride and carried out operations similar to those used in the first to third stages of Example 1 for the synthesis of methyl-( 2R)-1-[(E)-[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylideneamino]-2-methylpyrrolidine-2-carboxylate.

LCMS: m/z 412[M+H] ⁺

HPLC retention time: 0.95 min (assay conditions SMD-TFA05)

Second stage

Formula 60

(R)-1-((2,3-Difluoro-4-(2-morpholinoethoxy)benzylidene)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester was used and operations similar to those used in the first step of Comparative Example 1- 1, and (R)-1-((2,3-difluoro-4-(2-morpholinoethoxy)benzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester was obtained as a crude product.

LCMS: m/z 414[M+H] ⁺

HPLC retention time: 0.63 min (assay conditions SMD-TFA05)

Third stage

Formula 61

Methyl ester (R)-1-((2,3-difluoro-4-(2-morpholinoethoxy)benzyl)amino)-2-methylpyrrolidine-2-carboxylic acid and 3-butyloxy-3-propionic acid were used and operations were performed similar to those used in comparative example 1-2, for the synthesis of methyl ester (R)-1-(N-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2- methylpyrrolidine-2-carboxylic acid.

LCMS: m/z 556[M+H] ⁺

HPLC retention time: 1.03 min (assay conditions SMD-TFA05)

Fourth stage

We used (R)-1-(N-(2,3-Difluoro-4-(2-morpholinoethoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester and performed operations similar to those used in comparative example 1-2, for the synthesis of the desired compound.

LCMS: m/z 524[M+H] ⁺

HPLC retention time: 1.04 min (assay conditions SMD-TFA05)

The ester intermediates described in the table below were synthesized using the appropriate aldehyde reagents and proline derivatives using operations similar to those used in Comparative Example 1-1 or Comparative Example 1-2.

Comparative Example 13

4-(Trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]aniline

Formula 62

Toluene (900 ml), ethanol (226 ml), and water (450 ml) were added to 2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (60.00 g, 209 mmol), 5-bromo-2-(trifluoromethyl)pyridine (50.80 g, 225 mmol), tetrakis(triphenylphosphine) palladium (9.000 g, 7.79 mmol) and potassium carbonate (129.0 g, 930 mmol) under a nitrogen atmosphere and the mixture was stirred at 110°C for 3 hours. The reaction mixture was concentrated under reduced pressure, water (1,000 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (63 g, 98%).

LCMS: m/z 307[M+H] ⁺

HPLC retention time: 0.99 min (assay conditions SQD-AA05)

Comparative Example 14

2-Iodo-5-(2-methoxyethoxy)-4-(trifluoromethyl)aniline

Formula 63

First stage

Formula 64

2-Methoxyethanol (0.097 ml, 1.24 mmol) was dissolved in N-methylpyrrolidone (2 ml) under nitrogen, sodium hydride (60 wt.%, mineral oil dispersion, 30 mg, 1.24 mmol) was added and after stirring 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (0.118 mL, 0.823 mmol) was added to the mixture at room temperature over 30 minutes and the mixture was stirred at room temperature for 7 days. A 0.37 M aqueous solution of potassium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give 4-bromo-2-(2-methoxyethoxy)-1-(trifluoromethyl)benzene (231.2 mg, 94%).

HPLC retention time: 0.63 min (assay conditions SQD-AA50)

TLC (thin layer chromatography) (silica gel plate) Rf: 0.37 (10% ethyl acetate/hexane)

Second stage

Formula 65

4-Bromo-2-(2-methoxyethoxy)-1-(trifluoromethyl)benzene (231.2 mg, 0.773 mmol), carbamic acid tert-butyl ester (109 mg, 0.928 mmol), palladium (II) acetate (5, 21 mg, 0.023 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (33.2 mg, 0.07 mmol) and cesium carbonate (353 mg, 1.08 mmol ) was dissolved in 1,4-dioxane (5.2 ml) and the mixture was stirred under nitrogen atmosphere at 100°C overnight. A 0.37 M aqueous solution of potassium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give (3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (192.5 mg, 74% ).

LCMS: m/z 334 [M-H] ^-

HPLC retention time: 1.02 min (assay conditions SQD-AA05)

Third stage

Formula 66

Solution 4 N. Hydrogen chloride/1,4-dioxane (3.9 ml) was added to (3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (192.5 mg, 0.574 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ether/hexane (1/3) was added to the resulting residue, the precipitated solid was collected by filtration, and the resulting mixture was dried in vacuo to give 3-(2-methoxyethoxy)-4-(trifluoromethyl)aniline hydrochloride (128, 1 mg, 82%).

LCMS: m/z 236[M+H] ⁺

HPLC retention time: 0.83 min (assay conditions SQD-AA05)

Fourth stage

3-(2-Methoxyethoxy)-4-(trifluoromethyl)aniline hydrochloride (55.9 mg, 0.206 mmol) was dissolved in acetic acid (1.03 ml), N-iodosuccinimide (50.9 mg, 0.226 mmol) was added and the mixture was stirred at room temperature for 2 hours and 20 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, washed with 0.5 N. sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title compound (69.2 mg, 93%).

LCMS: m/z 362[M+H] ⁺

HPLC retention time: 1.19 min (assay conditions SMD-TFA05)

Comparative Example 15

2',3'-Dimethoxy-4-(2-methoxyethoxy)-5-(trifluoromethyl)-[1,1'-biphenyl]-2-amine

Formula 67

Toluene (2.7 ml) and ethanol (1.1 ml) were added to 2-iodo-5-(2-methoxyethoxy)-4-(trifluoromethyl)aniline (69.2 mg, 0.192 mmol), (2,3- dimethoxyphenyl)boronic acid (34.9 mg, 0.192 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (7.9 mg, 0.0096 mmol), then added 2 M aqueous solution of potassium carbonate (0. 38 ml) and the mixture was stirred under a nitrogen atmosphere at 100°C for 1 hour. A 0.37 M aqueous solution of potassium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title compound (41.1 mg, 58%).

LCMS: m/z 372[M+H] ⁺

HPLC retention time: 1.21 min (assay conditions SMD-TFA05)

The boronic acid derivatives and halides described in the table below were used and operations similar to those used in Comparative Example 13 or Comparative Example 15 were performed to synthesize the aniline intermediates described in the table below.

Comparative Example 63

6-(2-Amino-5-(trifluoromethyl)phenyl)pyrimidine-4-carbonitrile

Formula 68

2-(6-Chloropyrimidin-4-yl)-4-(trifluoromethyl)aniline (1.0 g, 3.65 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.246 g, 2.19 mmol) dissolved in dimethyl sulfoxide (3 ml), an aqueous solution (3 ml) of potassium cyanide (0.95 g, 14.6 mmol) was added at 0° C. and the mixture was stirred at room temperature overnight. A 0.37 M aqueous solution of potassium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography (40-100% acetonitrile/water) to give the title compound (365.6 mg, 38%).

LCMS: m/z 265[M+H] ⁺

HPLC retention time: 1.16 min (assay conditions SMD-TFA05)

Comparative Example 159

5-(2-Amino-5-(trifluoromethyl)phenyl)-4-methoxypyrimidine-2-carbonitrile

Formula 69

A mixture of 2-(2-chloro-4-methoxypyrimidin-5-yl)-4-(trifluoromethyl)aniline (89 mg, 0.293 mmol), zinc dicyanide (20.65 mg, 0.176 mmol), 1,1'-bis( diphenylphosphino)ferrocene (18.07 mg, 0.032 mmol) and tris(dibenzylideneacetone)dipalladium(0)⋅chloroform adduct (30.3 mg, 0.029 mmol) in N,N-dimethylformamide (1.5 ml) were heated and stirred in atmosphere nitrogen at 80°C for 1 hour. The reaction mixture was then heated and stirred at 110°C for 9 hours. The reaction mixture was purified using C18 reverse phase column chromatography (acetonitrile-water, 0.03% formic acid) to give 5-(2-amino-5-(trifluoromethyl)phenyl)-4-methoxypyrimidine-2-carbonitrile (57 mg, 66%).

LCMS: m/z 295[M+H] ⁺

HPLC retention time: 0.82 min (assay conditions SQD-FA05)

Comparative Example 65

6-(2-Amino-5-(trifluoromethyl)phenyl)-5-chloropyrimidine-4-carbonitrile

Formula 70

2-(5,6-dichloropyrimidin-4-yl)-4-(trifluoromethyl)aniline was used and operations similar to those used in Comparative Example 63 were performed to synthesize the title compound.

LCMS: m/z 299[M+H] ⁺

HPLC retention time: 0.82 min (assay conditions SQD-FA05)

Comparative Example 160

6-(2-Amino-5-(trifluoromethyl)phenyl)-5-methoxypyrimidine-4-carbonitrile

Formula 71

2-(6-chloro-5-methoxypyrimidin-4-yl)-4-(trifluoromethyl)aniline was used and operations similar to those used in Comparative Example 63 were performed to synthesize the title compound.

LCMS: m/z 295[M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Comparative Example 67

6-(2-Amino-5-(trifluoromethyl)phenyl)-5-methylpyrimidine-4-carbonitrile

Formula 72

2-(6-Chloro-5-methylpyrimidin-4-yl)-4-(trifluoromethyl)aniline was used and operations similar to those used in Comparative Example 63 were performed to synthesize the title compound.

LCMS: m/z 279[M+H] ⁺

HPLC retention time: 0.78 min (assay conditions SQD-FA05)

Comparative Example 68

5-(2-Amino-5-(trifluoromethyl)phenyl)pyrazine-2-carbonitrile

Formula 73

A mixture of 2-(5-bromopyrazin-2-yl)-4-(trifluoromethyl)aniline (27.6 mg, 0.087 mmol), zinc dicyanide (6.1 mg, 0.052 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.0043 mmol) in N,N-dimethylformamide (0.4 ml) was heated and stirred under nitrogen at 80°C for 18 hours. The reaction mixture was purified using C18 reverse phase column chromatography (acetonitrile- water, 0.03% formic acid) to obtain 5-(2-amino-5-(trifluoromethyl)phenyl)pyrazine-2-carbonitrile.

LCMS: m/z 265[M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Comparative Example 69

2-(6-Methylpyrimidin-4-yl)-4-(trifluoromethyl)aniline

Formula 74

2-(6-Chloropyrimidin-4-yl)-4-(trifluoromethyl)aniline (51.9 mg, 0.19 mmol), trimethylboroxine (0.053 ml, 0.379 mmol), bis(triphenylphosphine) palladium(II) chloride (13 .3 mg, 0.019 mmol) and potassium triphosphate (161 mg, 0.759 mmol) were dissolved in 1,4-dioxane (0.95 ml) and the mixture was stirred at 90°C for 1 hour. 0.37 M was added to the reaction mixture an aqueous potassium dihydrogen phosphate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title compound (27.4 mg, 57%).

LCMS: m/z 254[M+H] ⁺

HPLC retention time: 0.93 min (assay conditions SQD-AA05)

Comparative Example 162

2-(Trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine

Formula 75

First stage

Formula 76

Ethyl ester and 4-iodo-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used and operations similar to those used in Comparative Example 13 were performed to synthesize ethyl ester 2- (trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid.

LCMS: m/z 366[M+H] ⁺

HPLC retention time: 1.26 min (assay conditions SMD-TFA05)

Second stage

Formula 77

2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid ethyl ester obtained in the first step (36 mg, 0.10 mmol) was dissolved in a mixture of ethanol solution (1 ml) and water (1 ml) and sodium hydroxide (7.9 mg, 0.20 mmol) was added at room temperature. After stirring the mixture at room temperature for 1 hour, the solvent was concentrated under reduced pressure and 1 N was added to the residue. hydrochloric acid (5 ml). The resulting mixture was then extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid as a crude product (30 mg).

LCMS: m/z 338[M+H] ⁺

HPLC retention time: 1.05 min (assay conditions SMD-TFA05)

Third stage

N,N-dimethylformamide (1.5 ml) was added to 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-carboxylic acid obtained in the second step (30 mg, 0. 09 mmol), triethylamine (8.9 mg, 0.09 mmol) and diphenylphosphoryl azide (DPPA, 24.3 mg, 0.09 mmol) and the mixture was stirred at 60°C for 3 hours. Water (1 .5 ml) and the resulting mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, 1 N was added. aqueous sodium hydroxide solution and then the resulting mixture was extracted with ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (26 mg) as a crude product.

LCMS: m/z 309[M+H] ⁺

HPLC retention time: 1.08 min (assay conditions SMD-TFA05)

Comparative Example 71

4-Bromo-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

Formula 78

2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 4-chloro-6-(trifluoromethyl)pyrimidine were used as reagent and starting material, respectively, and similar operations were performed used in Comparative Example 13 to obtain 2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline. 1-Bromopyrrolidin-2,5-dione (66.2 mg, 0.372 mmol) was added to a solution of 2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (89 mg, 0.372 mmol) in acetic acid (0.94 ml)/water (0.0067 ml) at room temperature. The reaction mixture was heated at 55°C and stirred for 3.5 hours. The reaction mixture was cooled to room temperature and azeotroped three times with toluene. The residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to give the title compound (60 mg, 50%) as a yellow solid.

LCMS: m/z 318[M+H] ⁺

HPLC retention time: 1.24 min (assay conditions SMD-TFA05)

Example 21

(4aR)-1-[(2,3-Difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 79

2-Methylpropyl ether (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine -3-carboxylic acid (20 mg, 0.0567 mmol) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Comparative Example 50, 18 mg, 0.0596 mmol) were dissolved in toluene (0.2 ml) and the mixture was stirred at 90°C for 3.5 hours. The mixture was then allowed to cool, the filtrate was concentrated under reduced pressure and the resulting residue was purified using C18 reverse phase column chromatography (acetonitrile/water) and the desired compound was obtained (36 mg, 99%).

LCMS: m/z 628[M+H] ⁺

HPLC retention time: 1.17 min (assay conditions SQD-AA05)

Main tautomer

¹ H-NMR (CDC1 ₃ ) δ: 16.47 (1H, s), 12.91 (1H, s), 9.60 (1H, s), 8.47 (1H, d, J=8.7 Hz), 7.95 (1H, s), 7.90 (1H, s), 7.79 (1H, d, J=8.7 Hz), 7.13-7.10 (2H, m), 7.05-7.03 (1H, m), 5.08 (1H, d, J=14.3 Hz), 4.47 (1H, d, J=14.3 Hz), 3.33 (1H , ddd, J=9.0, 9.0, 3.2 Hz), 2.76 (1H, ddd, J=9.0, 8.7, 8.7 Hz), 2.56-2.54 (1H, m), 1.76-1.73 (1H, m), 1.69-1.64 (2H, m), 1.00 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 18.22 (1H, s), 12.98 (1H, s), 9.59 (1H, s), 8.33 (1H, d, J=8.7 Hz), 7.92 (2H, d, J=9.6 Hz), 7.79 (1H, d, J=8.7 Hz), 7.14-7.06 (3H, m), 5, 10 (1H, d, J=14.0 Hz), 4.52 (1H, d, J=14.6 Hz), 3.29-3.25 (1H, m), 2.78-2.75 (1H, m), 2.64-2.59 (1H, m), 1.73-1.66 (2H, m), 1.49-1.46 (1H, m), 0.84 (3H , s).

The appropriate aniline reagents of Comparative Examples 13 and 15-71 and the appropriate ester intermediates of Comparative Examples 1-1 and 1-2 and Comparative Examples 4-12 were used and operations similar to those used in Example 21 were performed to synthesize the compounds described in the table below . Note that in Examples 59 and 60, N,N-dimethylformamide was used as a solvent instead of toluene.

There are tautomers of the compounds described in this table. For example,

¹ H-NMR of examples 22 and 52 is as follows.

Example 22

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.12 (1H, s), 11.93 (1H, s), 9.35 (1H, s), 8.54 (1H, d, J=8.8 Hz) , 7.77 (1H, d, J=8.9 Hz), 7.59 (1H, s), 6.97 (1H, dd, J=7.8, 7.8 Hz), 6.76 ( 1H, dd, J=7.8, 7.8 Hz), 4.81 (1H, d, J=14.2 Hz), 4.32 (1H, d, J=14.3 Hz), 4, 20 (2Н, t, J=5.7 Hz), 3.74 (4Н, t, J=4.5 Hz), 3.29 (1Н, ddd, J=8.8, 8.7, 3, 0 Hz), 2.84 (2H, t, J=5.6 Hz), 2.67 (1H, ddd, J=8.8, 8.8, 8.8 Hz), 2.61-2, 59 (4H, m), 2.55-2.53 (1H, m), 2.45 (3H, s), 1.74-1.71 (1H, m), 1.67-1.62 ( 2H, m), 0.99 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 17.93 (1H, s), 12.03 (1H, s), 9.32 (1H, s), 8.36 (1H, d, J=8.9 Hz) , 7.77 (1H, d, J=8.9 Hz), 7.61 (1H, s), 7.06 (1H, dd, J=18.5, 10.0 Hz), 6.73 ( 1H, t,J=10.0 Hz), 5.00 (1H, d,J=14.4 Hz), 4.42 (1H, d, J=14.6 Hz), 4.19 (2H, q, J=6.7 Hz), 3.74 (4H, t, J=4.5 Hz), 3.24-3.22 (1H, m), 2.84 (2H, t, J=5 ,6 Hz), 2.70-2.66 (1H, m), 2.60 (4H, s), 2.55-2.49 (1H, m), 2.40 (ZN, s), 1 .67-1.62 (2H, m), 1.44-1.41 (1H, m), 0.79 (3H, s).

Example 52

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.13 (1H, s), 11.97 (1H, s), 8.87 (1H, d, J=5.0 Hz), 8.46 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.74 (1H, d, J=8.6 Hz), 7.60 (1H, d, J=4.9 Hz) , 7.53 (1H, s), 6.99 (1H, dd, J=7.8, 7.8 Hz), 6.78 (1H, dd, J=7.8, 7.8 Hz), 4, 83 (1H, d, J=14.3 Hz), 4.31 (1H, d, J=14.3 Hz), 4.20 (2H, t, J=5.7 Hz), 3.74 ( 4H, t, J=4.2 Hz), 3.31 (1H, ddd, J=8.8, 8.8, 3.0 Hz), 2.85-2.83 (2H, m), 2 .69 (1H, ddd, J=8.8, 8.8, 8.8 Hz), 2.61 (4H, brs), 2.56-2.51 (1H, m), 1.75-1 .72 (1H, m), 1.67-1.65 (2H, m), 0.99 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 17.91 (1H, s), 12.05 (1H, s), 8.82 (1H, d, J=4.9 Hz), 8.24 (1H, d, J=8.5 Hz), 7.77 (1H, s), 7.74 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=5.0 Hz) , 7.54 (1H, brs), 7.06 (1H, t, J=7.8 Hz), 6.73 (1H, t, J=7.7 Hz), 5.01 (1H, d, J= 14.4 Hz), 4.43 (1H, d, J=14.5 Hz), 4.19 (2H, dd, J=12.1, 6.2 Hz), 3.74 (4H, t, J=4.2 Hz), 3.27-3.24 (1H, m), 2.84 (2H, s), 2.74-2.72 (1H, m), 2.61 (3H, brs ), 2.50-2.46 (1H, m), 1.78-1.63 (3H, m), 1.45-1.42 (1H, m), 0.81 (3H, s).

Example 109

(4aR)-N-[2-(5-Cyano-6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 80

(4aR)-N-[2-(6-Chloro-5-cyanopyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- Methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68) was used as the starting material and operations similar to those used in Comparative Example 69 were performed to obtain the desired compound.

LCMS: m/z 598[M+H] ⁺

HPLC retention time: 1.63 min (assay conditions QC-SMD-TFA05)

Example 110

(4aR)-1-[(2,3-(Difluorophenyl)methyl]-N-[2-[1-(dimethylsulfamoyl)piperidin-4-yl]-4-(trifluoromethyl)phenyl]-4-hydroxy-4a- methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 81

First stage

Formula 82

2-Bromo-4-(trifluoromethyl)aniline and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid were used as reagent and starting material, respectively, and operations similar to those used were performed. in Comparative Example 13, and 4-(2-amino-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was obtained.

LCMS: m/z 243[M+H-C ₄ H ₉ OCO] ⁺

HPLC retention time: 1.31 min (assay conditions SMD-TFA05)

Second stage

Formula 83

The aniline derivative obtained in the first stage (0.73 g, 2.13 mmol) was dissolved in methanol (21.2 ml), palladium hydroxide on carbon was added (20 wt.%, 0.15 g, 0.21 mmol) and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give 4-(2-amino-5-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (0.70 g, 91%) as unrefined product.

Third stage

Formula 84

The aniline derivative obtained in the second step and the compound described in Comparative Example 1-1 were used as a reagent and raw material, respectively, and operations similar to those in Example 21 were performed to obtain 4-[2-[[ tert-butyl ether (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carbonyl ]amino]-5-(trifluoromethyl)phenyl]piperidine-1-carboxylic acid.

LCMS: m/z 565[M+H-C ₄ H ₉ OС] ⁺

HPLC retention time: 1.78 min (assay conditions SMD-TFA05)

Fourth stage

Formula 85

4 n. A hydrogen chloride/dioxane solution (5 mL) at 0° C. was added to the amide derivative obtained in the third step (0.81 g, 1.23 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. pressure and obtained (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-piperidin-4-yl-4-(trifluoromethyl)phenyl] -6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide hydrochloride (776 mg) as a yellow amorphous solid.

LCMS: m/z 565[M+H] ⁺

HPLC retention time: 1.24 min (assay conditions SMD-TFA05)

Fifth stage

The hydrochloride obtained in the fourth step (0.030 g, 0.050 mmol) was dissolved in N,N-dimethylformamide (0.25 ml) and then triethylamine (0.021 ml, 0.15 mmol) and dimethylsulfamoyl chloride (0.0054 ml) were added at room temperature , 0.050 mmol) and the mixture was stirred for 2 hours. The reaction mixture was immediately purified using C18 reverse phase column chromatography (acetonitrile/water) to obtain the title compound (24 mg, 71%) as a white amorphous solid.

LCMS: m/z 672[M+H] ⁺

HPLC retention time: 1.66 min (assay conditions QC-SMD-TFA05)

Example 111

(4aR)-N-[2-[5-Cyano-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]-4-(trifluoromethyl)phenyl]-1- [(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 86

(4aR)-N-[2-(6-Chloro-5-cyanopyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- Methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68) (20 mg, 0.032 mmol) was dissolved in 1,2-dichloroethane (0.32 ml ) under a nitrogen atmosphere, 2-oxa-6-azaspiro[3.3]heptane oxalate (24.5 mg, 0.129 mmol) and N,N-diisopropylethylamine (0.068 ml, 0.388 mmol) were added and the mixture was stirred at room temperature overnight and at 60°C for 2 days. 0.37 M aqueous potassium dihydrogen phosphate and dichloromethane were added to the reaction mixture, the mixture was vigorously stirred, and then the aqueous layer was separated using a phase separator, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography (30-95% acetonitrile/water) to give the title compound (19.7 mg, 89%).

LCMS: m/z 681[M+H] ⁺

HPLC retention time: 0.99 min (SMD-TFA50 assay conditions)

Example 112

Methyl 2-[[5-[2-[[(4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazin-3-carbonyl]amino]-5-(trifluoromethyl)phenyl]-3-cyanopyridin-2-yl]-methylamino]acetate

Formula 87

N-methylglycine methyl ester was used as a reagent and operations similar to those used in Example 111 were performed to synthesize the desired compound.

LCMS: m/z 685[M+H] ⁺

HPLC retention time: 1.65 min (assay conditions QC-SMD-TFA05)

Example 113

(4aR)-N-[2-(6-Cyano-5-methylsulfanylpyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 88

(4aR)-N-[2-(6-Cyano-5-nitropyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- Methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 99) (26.1 mg, 0.042 mmol) was dissolved in N,N-dimethylformamide (0. 3 ml), sodium thiomethoxide (2.91 mg, 0.042 mmol) was added and the mixture was stirred at room temperature for 3 days. A 0.37 M aqueous solution of potassium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography (30-90% acetonitrile (0.1% formic acid)/water (0.1% formic acid) to give the title compound (17.7 mg, 49%).

LCMS: m/z 630[M+H] ⁺

HPLC retention time: 1.04 min (SMD-TFA50 assay conditions)

Example 114

(4aR)-N-[2-(6-Cyano-5-methoxypyridin-3-yl)-4-(trifluoromethyl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a- methyl 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 89

Sodium methoxide was used as a reagent and operations similar to those used in Example 113 were performed to synthesize the desired compound.

LCMS: m/z 614[M+H] ⁺

HPLC retention time: 1.62 min (assay conditions QC-SMD-TFA05)

Comparative Example 72

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-1 -yl]methyl]-2,3-difluorophenyl]hept-6-inoate

Formula 90

A suspension of 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazine-3-carboxylic acid (comparative example 5) (250 mg, 0.480 mmol), hept-6-ynic acid (0.182 ml, 1.44 mmol), copper(1) iodide (18.3 mg, 0.0960 mmol), triethylamine (0.335 ml, 2.40 mmol), and bis(triphenylphosphine) palladium(II) chloride (33.7 mg, 0.0480 mmol) in tetrahydrofuran (0.961 ml) were stirred under a nitrogen atmosphere at room temperature for 2.5 hours. Simultaneously, the exact same reaction was carried out in another vessel on the same scale and both products were combined and purified using C18 reverse phase column chromatography to obtain the title compound (328 mg, 66%) as a yellow oil .

LCMS: m/z 519[M+H] ⁺

HPLC retention time: 1.00 min (assay conditions SQD-FA05)

Comparative Example 73

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-1 -yl]methyl]-2,3-difluorophenyl]heptanoate

Formula 91

A solution of 7-[4-[[(4aR)-4-hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 1-yl]methyl]-2,3-difluorophenyl]hept-6-ynic acid (Comparative Example 72) (358 mg, 0.69 mmol) and palladium hydroxide on carbon (20 wt.%, approximately 50% moistened with water , 145 mg) in 2,2,2-trifluoroethanol (7 ml) was stirred under hydrogen atmosphere at room temperature for 2 hours. Palladium hydroxide on carbon (20 wt.%, approximately 50% wetted with water, 145 mg) was then added. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered through a pad of celite, and the filtrate was concentrated to give the title compound (361 mg, 100%) as a light brown oil.

LCMS: m/z 523[M+H] ⁺

HPLC retention time: 1.05 min (assay conditions SQD-AA05)

Example 115

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-[[2-(6-methylsulfanylpyridin-3-yl)-4-(trifluoromethyl)phenyl]carbamoyl]-2-oxo-6 ,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]heptanoate

Formula 92

We used 7-[4-[[(4aR)-4-hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 1-yl]methyl]-2,3-difluorophenyl]heptanoate (comparative example 73) and 2-(6-(methylthio)pyridin-3-yl)-4-(trifluoromethyl)aniline and carried out operations similar to those used in example 21 , to synthesize the desired compound.

LCMS: m/z 733[M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SQD-FA05)

Example 116

7-[4-[[(4aR)-3-[[4-Chloro-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl]-4-hydroxy-4a-methyl-2-oxo- 6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]heptanoate

Formula 93

We used 7-[4-[[(4aR)-4-hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 1-yl]methyl]-2,3-difluorophenyl]heptanoate (comparative example 73) and 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)aniline and carried out operations similar to those used in example 21 to synthesis of the desired compound.

LCMS: m/z 721[M+H] ⁺

HPLC retention time: 1.22 min (assay conditions SQD-FA05)

Example 117

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-[[2-(6-methylsulfanylpyridin-3-yl)-4-(trifluoromethyl)phenyl]carbamoyl]-2-oxo-6 ,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]hept-6-inoate

Formula 94

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-1 -yl]methyl]-2,3-difluorophenyl]hept-6-ynic acid (Comparative Example 72) was used as the starting material, 2-(6-(methylthio)pyridin-3-yl)-4-(trifluoromethyl)aniline was used as a reagent and operations similar to those used in example 21 were performed to synthesize the desired compound.

LCMS: m/z 729[M+H] ⁺

HPLC retention time: 1.61 min (assay conditions SMD-TFA05)

Example 118

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-[[2-(2-methylsulfanylpyrimidin-5-yl)-4-(trifluoromethyl)phenyl]carbamoyl]-2-oxo-6 ,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]hept-6-inoate

Formula 95

We used 7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 1-yl]methyl]-2,3-difluorophenyl]hept-6-ynic acid (Comparative Example 72) and 2-(2-(methylthio)pyrimidin-5-yl)-4-(trifluoromethyl)aniline and operations were carried out, similar to those used in example 21, for the synthesis of the desired compound.

LCMS: m/z 730[M+H] ⁺

HPLC retention time: 1.58 min (assay conditions SMD-TFA05)

Example 119

7-[4-[[(4aR)-4-Hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[5-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl ]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]hept-6-inoate

Formula 96

We used 7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-(2-methylpropoxycarbonyl)-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 1-yl]methyl]-2,3-difluorophenyl]hept-6-ynic acid (Comparative Example 72) and 4-(trifluoromethyl)-2-(5-(trifluoromethyl)pyridin-3-yl)aniline and operations were carried out, similar to those used in example 21, for the synthesis of the desired compound.

LCMS: m/z 751[M+H] ⁺

HPLC retention time: 1.60 min (assay conditions SMD-TFA05)

Comparative Example 74

2-Methylpropyl ether (4aR)-1-[[4-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]butoxy]-2,3-difluorophenyl] methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid Formula 97

First stage

Formula 98

4-(Benzyloxy)-2,3-difluorobenzaldehyde and (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride were used as the reagent and starting material, respectively, and operations similar to those used in the first step of Example 1 and Comparative Example were performed 1-1, for the synthesis of 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-phenylmethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H -pyrrolo[1,2-b]pyridazine-3-carboxylic acid.

Second stage

Formula 99

Palladium on carbon (10 wt.%, 120 mg) was added to a solution of 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-phenylmethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2- oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (1.56 g, 3.12 mmol) in ethyl acetate (100 ml) and the mixture was stirred under hydrogen atmosphere at room temperature within 30 min. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-hydroxyphenyl)methyl ]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (1.02 g, 80%).

LCMS: m/z 411[M+H] ⁺

HPLC retention time: 1.24 min (assay conditions SMD-TFA05)

Third stage

Formula 100

A 60% sodium hydroxide solution (2 mL, 30.3 mmol) was added to a mixture of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2.00 g, 15.1 mmol) and 1,4-dibromobutane (5.42 ml, 45.4 mmol). Tetrabutylammonium hydrogen sulfate (257 mg, 0.757 mmol) was added to this mixture and the resulting mixture was stirred vigorously at room temperature overnight. Water was then added, the layer was extracted four times with hexane/diethyl ether (1:4) and the organic layers were combined and dried over magnesium sulfate. The resulting mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (S)-4-((4-bromobutoxy)methyl)-2,2-dimethyl-1,3 -dioxolane (2.54 g, 63%) as a colorless oil.

Fourth stage

Cesium carbonate (1.20 mg, 3.65 mmol) was added to a solution of 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2 -oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (500 mg, 1.22 mmol) and (S)-4-((4-bromobutoxy)methyl)- 2,2-dimethyl-1,3-dioxolane (374 mg, 1.40 mmol) in acetonitrile (15.2 ml) and the mixture was stirred at 70°C for 1 hour. The mixture was then cooled to room temperature, 0. A 37 M aqueous solution of potassium dihydrogen phosphate and the aqueous layer were extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over magnesium sulfate. The resulting mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (414 mg, 57%).

LCMS: m/z 597[M+H] ⁺

HPLC retention time: 1.52 min (assay conditions SMD-TFA05)

Example 120

(4aR)-1-[[4-[4-[(2R)-2,3-Dihydroxypropoxy]butoxy]-2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-N-[2-( 6-methylsulfanylpyridin-3-yl)-4-(trifluoromethyl)phenyl]-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 101

2-Methylpropyl ether (4aR)-1-[[4-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]butoxy]-2,3-difluorophenyl] methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (Comparative Example 74) (10.6 mg, 0.018 mmol ) and 2-(6-(methylthio)pyridin-3-yl)-4-(trifluoromethyl)aniline (5.1 mg, 0.018 mmol) were dissolved in toluene (0.5 ml) and the mixture was stirred at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in methanol (0.5 ml), p-toluenesulfonic acid monohydrate (3.4 mg, 0.018 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resulting white cloudy solution was purified using C18 reverse phase column chromatography (30-90% acetonitrile (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid)) to obtain the title compound (6 .3 mg, 46%) as a light brown amorphous solid.

LCMS: m/z 767[M+H] ⁺

HPLC retention time: 1.51 min (assay conditions QC-SMD-TFA05)

Example 121

(4aR)-N-[4-Chloro-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-1-[[4-[4-[(2R)-2,3-dihydroxypropoxy]butoxy] -2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 102

We used 2-methylpropyl ether (4aR)-1-[[4-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]butoxy]-2,3-difluorophenyl ]methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (Comparative Example 74) and 4-chloro-2- (6-(trifluoromethyl)pyridin-3-yl)aniline and carried out operations similar to those used in example 120 to synthesize the desired compound.

LCMS: m/z 755[M+H] ⁺

HPLC retention time: 1.50 min (assay conditions QC-SMD-TFA05)

Example 122

(4aR)-N-[4-Bromo-2-(6-chloropyridin-3-yl)phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo- 6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 103

Dimethoxyethane (0.2 ml), ethylene glycol (0.2 ml), and water (0.1 ml) were added to (4aR)-N-(4-bromo-2-iodophenyl)-1-[(2,3- difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 331) (14.8 mg, 0. 02 mmol), potassium carbonate (9.7 mg, 0.07 mmol), tetrakis(triphenylphosphine) palladium (2.3 mg, 0.002 mmol) and (6-chloropyridin-3-yl)boronic acid (3.1 mg, 0.02 mmol) and the mixture was stirred at 100°C for 2 hours. Insoluble substances were filtered off and the filtrate was immediately purified using HPLC (YMC-Actus ODS-A 20×100 mm 0.005 mm, 0.1% formic acid-acetonitrile/ 0.1% formic acid-water) to obtain the title compound (4.8 mg, 40%) as a white amorphous solid.

LCMS: m/z 604[M+H] ⁺

HPLC retention time: 0.89 min (assay conditions SQD-FA05)

Comparative Example 75

((4S,5S)-5-((Hept-6-in-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol

Formula 104

Sodium hydride (60 wt.%, dispersion in mineral oil, 36 mg, 0.824 mmol) was added to the solution of ((4S,5S)-2,2-dimethyl-1,3-dioxolan-4,5-diyl) at room temperature. dimethanol (133 mg, 0.824 mmol) in N,N-dimethylformamide (1.1 ml). After stirring the reaction mixture at room temperature for 30 minutes, hept-6-yn-1-ylmethanesulfonate (105 mg, 0.550 mmol) was added and the mixture was stirred at room temperature overnight. Water was slowly added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ((4S,5S)-5-((hept-6-yn-1-yloxy)methyl)-2,2-dimethyl-1 ,3-dioxolan-4-yl)methanol (99.6 mg, 71%).

Comparative Example 76

(C)-4-((3-Bromopropoxy)methyl)-2,2-dimethyl-1,3-dioxolane

Formula 105

(R)-(-)-2,2-Dimethyl-1,3-dioxolane-4-methanol (615 mg, 4.66 mmol), 6-bromo-1-hexine (500 mg, 3.1 mmol) was dissolved in N,N-dimethylformamide (10 ml), sodium hydride (60 wt.%, dispersion in mineral oil, 186 mg, 4.66 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added to water and extracted with diethyl ether. The organic layer was then washed with brine and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (R)-4-((hex-5-yn-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolane (390 mg, 59%) in the form of a clear liquid.

¹ H-NMR (CDCl ₃ ) δ: 4.24 (1H, dt, J=12.0, 6.4 Hz), 4.04 (1H, dd, J=8.0, 6.4 Hz), 3.71 (1H, dd, J=8.3, 6.4 Hz), 3.54-3.44 (3H, m), 3.41 (1H, dd, J=11.0, 5.0 Hz), 2.20 (4H, td, J=7.0, 3.0 Hz), 1.92 (4H, t, J=3.0 Hz), 1.72-1.64 (2H, m ), 1.62-1.53 (2H, m), 1.40 (3H, s), 1.34 (3H, s).

Comparative Example 77

4-(Prop-2-yn-1-yl)morpholin-3-one

Formula 106

Sodium hydride (60 wt.%, dispersion in mineral oil, 187 mg, 4.68 mmol) was added at 0°C to a solution of morpholin-3-one (430 mg, 4.25 mmol) in tetrahydrofuran (5 ml) and the mixture stirred at room temperature for 10 minutes and 3-bromoprop-1-yne (607 mg, 5.1 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and then the reaction mixture was washed successively with saturated aqueous ammonium chloride, water and brine and dried over magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (312 mg, 53%) as a clear oil.

¹ H-NMR (CDCl ₃ ) δ: 4.29 (2H, d, J=2.4 Hz), 4.19 (2H, s), 3.93 (2H, t, J=5.2 Hz) , 3.51 (2H, t,J=5.2 Hz), 2.25 (1H, m).

Example 123

(4aR)-1-[[2,3-Difluoro-4-[3-(4-hydroxybutoxy)prop-1-ynyl]phenyl]methyl]-N-[2-(2,3-dimethoxyphenyl)-4- (trifluoromethyl)phenyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 107

4-(Prop-2-yn-1-yloxy)butan-1-ol (15.5 mg, 0.121 mmol) and triethylamine (0.020 ml, 0.141 mmol) were added to the (4aR)- solution under a nitrogen atmosphere at 0°C 1-[2,3-(difluoro-4-iodophenyl)methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4-hydroxy-4a-methyl-2-oxo- 6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (example 321) (30 mg, 0.040 mmol), bis(triphenylphosphine) palladium(P) chloride (2.83 mg, 0. 0404 mmol) and copper(I) iodide (1.54 mg, 0.0081 mmol) in N,N-dimethylformamide (0.40 ml). The reaction mixture was stirred at room temperature for 14 hours. Formic acid was added to the reaction mixture and the mixture was immediately purified by C18 reverse phase column chromatography to obtain the title compound (15 mg, 50%) as a white amorphous solid.

LCMS: m/z 744[M+H] ⁺

HPLC retention time: 1.63 min (assay conditions QC-SMD-TFA05)

Example 124

(4aR)-1-[[2,6-Difluoro-4-[7-[(2S,3S)-2,3,4-trihydroxybutoxy]hept-1-ynyl]phenyl]methyl]-4-hydroxy-4a -methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine -3-carboxamide

Formula 108

((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (23.9 mg, 0.093 mmol) and triethylamine (0.019 ml, 0.140 mmol) in a nitrogen atmosphere at 0° C was added to the solution of (4aR)-1-[(2,6-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6 -(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 322) (35 mg, 0.047 mmol), bis(triphenylphosphine) palladium(II) chloride (3.27 mg, 0.0465 mmol) and copper(I) iodide (1.77 mg, 0.0093 mmol), in N,N-dimethylformamide (0.47 ml). The reaction mixture was stirred at room temperature overnight. Trifluoroacetic acid/water (1:1, 1.4 ml) and dimethyl sulfoxide (0.7 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. The reaction mixture was immediately purified using C18 reverse phase column chromatography and the title compound (32 mg, 82%) was obtained as an orange amorphous solid.

LCMS: m/z 841[M+H] ⁺

HPLC retention time: 0.90 min (assay conditions SMD-TFA50)

Example 125

(4aR)-1-[[2,6-Difluoro-4-[7-[(2S,3S)-2,3,4-trihydroxybutoxy]heptyl]phenyl]methyl]-4-hydroxy-4a-methyl-2 -oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 109

A suspension of (4aR)-1-[[2,6-difluoro-4-[7-[(2S,3S)-2,3,4-trihydroxybutoxy]hept-1-ynyl]phenyl]methyl]-4-hydroxy- 4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)-pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b ]pyridazine-3-carboxamide (example 124) (20 mg, 0.024 mmol) and palladium hydroxide on carbon (20 wt.%, 3.34 mg, 0.00476 mmol) in ethyl acetate were stirred under a hydrogen atmosphere at room temperature for 10 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography to give the title compound (11.5 mg, 57%) as a colorless amorphous solid.

LCMS: m/z 845[M+H] ⁺

HPLC retention time: 1.60 min (assay conditions QC-SMD-TFA05)

Example 126

(4aR)-1-[(4-Ethynyl-2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 110

Triisopropylsilylacetylene was used as a reagent and operations similar to those used in the first step of Example 123 were performed to obtain (4aR)-1-[[2,3-difluoro-4-[2-tri(propan-2-yl)silylethynyl]phenyl] methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo [1,2-b]pyridazine-3-carboxamide as a crude product. The resulting crude product was dissolved in tetrahydrofuran (0.15 ml), a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.12 ml) was added and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (0.5 ml) was added to the reaction mixture. water (0.5 ml) and dimethyl sulfoxide (1 ml) and the mixture was purified by C18 reverse phase column chromatography to give the title compound (22 mg, 84%) as a white amorphous solid.

LCMS: m/z 652[M+H] ⁺

HPLC retention time: 0.87 min (assay conditions SQD-FA50).

The appropriate iodide derivatives of Examples 319-323 and suitable alkyne terminal reagents were used and operations similar to those used in Example 123 were performed to synthesize the compounds described in the table below.

Although tautomers exist for some of the compounds described in this table, isomers may be observed in some cases but not others depending on the type of solvent used for the measurement.

For example, ¹ H-NMR of Example 129 (dimethyl sulfoxide-D6) and Example 140 (chloroform-D) is as follows.

Example 129

¹ H-NMR (DMSO-D ₆ ) δ: 16.58 (1H, brs), 12.80 (1H, brs), 12.15 (1H, brs), 9.59 (1H, s), 8, 59-8.56 (1H, brm), 8.48-8.38 (1H, m), 8.27 (1H, brs), 7.99 (1H, d, J=9.8 Hz), 7 .28 (1H, q, J=6.8 Hz), 7.24 (1H, q, J=7.3 Hz), 5.11 (1H, d, J=14.7 Hz), 4.47 -4.38 (1H, m), 3.41-3.30 (2H, m), 2.73 (1H, q, J=8.6 Hz), 2.54 (2H, t, J=6 ,4 Hz), 2.49-2.36 (1H, m), 2.40 (2H, t, J=7.8 Hz), 1.84-1.75 (2H, m), 1.63 (2H, brs), 0.92 (3H, brs).

Example 140

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 11.82 (1H, s), 8.78 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=8.6 Hz) , 7.97 (1H, dd, J=8.1, 1.9 Hz), 7.86 (1H, d, J=8.2 Hz), 7.73 (1H, dd, J=8.7 , 1.9 Hz), 7.56 (1H, d, J=1.8 Hz), 7.15-7.11 (1H, m), 6.98-6.94 (1H, m), 4 .84 (1H, d, J=14.3 Hz), 4.32 (1H, d, J=13.9 Hz), 3.85-3.79 (4H, m), 3.68 (2H, s), 3.27 (1H, td, J=8.7, 3.2 Hz), 2.83-2.77 (4H, m), 2.73-2.64 (1H, m), 2 .58-2.48 (1H, m), 1.80-1.58 (3H, m), 0.99 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 11.91 (1H, s), 8.72 (1H, d, J=2.2 Hz), 8.19 (1H, d, J=8.2 Hz) , 7.96-7.92 (1H, m), 7.80 (1H, d, J=8.2 Hz), 7.75-7.71 (1H, m), 7.58-7.55 (1H, m), 7.17-7.07 (1H, m), 6.99-6.93 (1H, m), 5.07 (1H, d, J=14.7 Hz), 4, 47 (1H, d, J=14.9 Hz), 3.79-3.85 (4H, m), 3.67 (2H, s), 3.30-3.20 (1H, m), 2 .83-2.77 (4H, m), 2.73-2.64 (1H, m), 2.58-2.48 (1H, m), 1.81-1.58 (3H, m) , 0.79 (3H, s).

The appropriate iodide derivatives of Examples 319-323 and suitable alkyne terminal reagents were used and operations similar to those used in Example 123 and Example 125 were performed to synthesize the compounds described in the table below.

Suitable iodide derivatives of Examples 319-323 and suitable alkyne terminal reagents, including those used in Comparative Example 76, were used and operations similar to those used in Example 124 were performed to synthesize the compounds described in the table below.

Example 146

(4aR)-1-[[2,6-Dichloro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-(trifluoromethyl) -4-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide hydrochloride

Formula 111

(4aR)-1-[(2,6-Dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-(trifluoromethyl)-4-[6-(trifluoromethyl) pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide (Example 328) (22 mg, 0.032 mmol), 4-(2 -chloroethyl)morpholine hydrochloride (12.1 mg, 0.065 mmol) and tetra-n-butylammonium iodide (1.2 mg, 0.0033 mmol) were dissolved in N,N-dimethylformamide (0.2 ml), cesium carbonate (64 mg) was added , 0.20 mmol) and the mixture was stirred under a nitrogen atmosphere at 60°C for 3 hours. Dimethyl sulfoxide (0.4 ml) and concentrated hydrochloric acid (0.1 ml) were added to the reaction mixture at 0°C and after stirring the mixture within 5 min, the resulting mixture was immediately purified by C18 reverse phase column chromatography on silica gel (water/acetonitrile) to obtain the title compound (23 mg, 88%) as a white amorphous solid.

LCMS: m/z 790[M+H] ⁺

HPLC retention time: 1.26 min (assay conditions SMD-TFA05)

Example 147

(4aR)-1-[[4-[3-[(2R)-2,3-Dihydroxypropoxy]propoxy]-2,3-difluorophenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N- [4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 112

First stage

Formula 113

Water (10 ml) and sodium hydroxide (1.75 g, 43.8 mmol) were added to 1,3-dibromopropane (9.17 g, 45.4 mmol), (S)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methanol (1.5 g, 11.4 mmol) and tetra-n-butylammonium hydrogen sulfate (0.19 g, 0.57 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. Water (30 ml) was added to the reaction mixture, and then the resulting mixture was extracted with diethyl ether, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (S)-4-((3-bromopropoxy)methyl)-2,2-dimethyl-1,3-dioxolane (640 mg, 22%) in the form of a clear liquid.

Second stage

(4aR)-1-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide (Example 324) (1.0 g, 1.56 mmol) and (S)- 4-((3-bromopropoxy)methyl)-2,2-dimethyl-1,3-dioxolane (0.47 g, 1.87 mmol) was dissolved in N,N-dimethylformamide (3 ml), cesium carbonate (0 86 g, 6.23 mmol) and the mixture was stirred under nitrogen atmosphere at 80°C for 2 hours. Diethyl ether (30 ml) was added to the reaction mixture and insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. Methanol (10 ml) was then added to the resulting residue, concentrated hydrochloric acid (2 ml) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purged with nitrogen for 1 hour to remove excess hydrogen chloride and then dimethyl sulfoxide (5 ml) was added, methanol was removed under reduced pressure and the resulting residue was purified by C18 reverse phase column chromatography on silica gel (water/acetonitrile) to obtain the title compound (1.2 g, 95%) as a white amorphous solid matter.

LCMS: m/z 775 [M+H] ⁺

HPLC retention time: 1.49 min (assay conditions SMD-TFA05)

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.21 (1H, s), 11.91 (1H, s), 8.78 (1H, s), 8.44 (1H, d, J=8.7 Hz), 7.98 (1H, d, J=8.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=8.7 Hz) , 7.55 (1H, s), 6.92 (1H, dd, J=7.8, 7.5 Hz), 6.71 (1H, dd, J=7.8, 7.5 Hz), 4.73 (1H, d, J=14.2 Hz), 4.30 (1H, d, J=14.2 Hz), 4.14 (2H, t, J=6.2 Hz), 3, 89-3.87 (1H, m), 3.72-3.69 (3H, m), 3.65-3.64 (1H, m), 3.57-3.54 (2H, m), 3.27-3.24 (1H, m), 2.70-2.62 (1H, m), 2.56-2.55 (1H, m), 2.53-2.50 (1H, m ), 2.12-2.08 (3H, m), 1.73-1.70 (1H, m), 1.67-1.61 (2H, m), 1.00 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 17.97 (1H, s), 11.89 (1H, s), 8.71 (1H, s), 8.19 (1H, d, J=8.6 Hz), 7.94 (1H, d, J=7.9 Hz), 7.79 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=8.6 Hz) , 7.55 (1H, s), 7.06-7.04 (1H, m), 6.73-6.70 (1H, m), 4.99 (1H, d, J=14.4 Hz ), 4.42 (1H, d, J=14.4 Hz), 4.14 (2H, t, J=6.2 Hz), 3.89-3.88 (1H, m), 3.72 -3.69 (3H, m), 3.65-3.64 (1H, m), 3.57-3.54 (2H, m), 3.25-3.24 (1H, m), 2 .70-2.62 (2H, m), 2.41-2.39 (1H, m), 2.12-2.08 (3H, m), 1.67-1.61 (2H, m) , 1.43-1.37 (1H, m), 0.77 (3H, s).

Comparative Example 78

(S)-4-(((5-Bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane

Formula 114

1,5-Dibromopentane and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol were used and operations similar to those used in the first step of Example 147 were performed to obtain (S)-4-( (hex-5-yn-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolane as a clear liquid.

¹ H-NMR (CDCl ₃ ) δ: 4.25 (1H, dt, J=12.0, 6.0 Hz), 4.05 (1H, dd, J=6.4, 8.0 Hz), 3.72 (1H, dd, J=6.4, 8.0 Hz), 3.53-3.37 (6H, m), 1.87 (2H, dt, J=14.2, 7.1 Hz), 1.64-1.54 (2H, m), 1.54-1.44 (2H, m), 1.41 (3H, s), 1.35 (3H, s).

Comparative Example 79

(R)-4-(((5-Bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane

Formula 115

1,5-Dibromopentane and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol were used and operations similar to those used in the first step of Example 147 were performed to obtain (R)-4- (((5-Bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane.

Example 148

(4aR)-1-[[2,6-Dichloro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[6-(trifluoromethyl) -2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide hydrochloride

Formula 116

We used (4aR)-1-[(2,6-dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[6-(trifluoromethyl)-2-[6-(trifluoromethyl )pyridin-3-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide (Example 329) and 4-(2-chloroethyl)morpholine hydrochloride and carried out operations similar to those used in example 146 for the synthesis of the desired compound.

LCMS: m/z 789[M+H] ⁺

HPLC retention time: 1.29 min (assay conditions QC-SMD-TFA05)

Example 149

(4aR)-1-[[3-Chloro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2 -[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 117

First stage

Formula 118

4-(Benzyloxy)-3-chlorobenzaldehyde and (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride were used and operations similar to those used in Comparative Example 4 were performed to synthesize (4aR)-1-[2-methylpropyl ester (3-chloro-4-phenylmethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid.

Second stage

Formula 119

We used 2-methylpropyl ether (4aR)-1-[(3-Chloro-4-phenylmethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2- b]pyridazine-3-carboxylic acid and carried out operations similar to those used in the second step of Comparative Example 74 to synthesize 2-methylpropyl ester (4aR)-1-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy- 4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid.

Third stage

Formula 120

We used 2-methylpropyl ether (4aR)-1-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2- b]pyridazin-3-carboxylic acid and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Comparative Example 13) and carried out operations similar to those used in Example 21 to synthesize (4aR) -1-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl ]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide.

Fourth stage

We used (4aR)-1-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridine -3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide and 4-(2-chloroethyl)morpholine hydrochloride and carried out operations similar to those used in example 146 for the synthesis the desired connection.

LCMS: m/z 754[M+H] ⁺

HPLC retention time: 1.32 min (assay conditions QC-SMD-TFA05)

Example 150

Methyl 2-[4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl ]carbamoyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenoxy] acetate

Formula 121

First stage

Formula 122

We used (4aR)-1-[(2,3-difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-H-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide (example 324) and bromoacetic acid tert-butyl ester and carried out operations similar to those used in the example 146, for the synthesis of tert-butyl ester 2-[4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridine - 3-yl]phenyl]carbamoyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenoxy]acetic acid.

LCMS: m/z 757[M+H] ⁺

HPLC retention time: 1.23 min (assay conditions SQD-FA05)

Second stage

Formula 123

Trifluoroacetic acid (0.3 ml, 4 mmol) was added to the solution of 2-[4-[[(4aR-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)- 2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenoxy] acetic acid (14.7 mg, 0.019 mmol) in dichloromethane (0.075 ml) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using reverse phase column chromatography (0 .1% formic acid, acetonitrile/water) to obtain 2-[4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenoxy]acetic acid (12, 3 mg, 90%).

LCMS: m/z 701[M+H] ⁺

HPLC retention time: 1.08 min (assay conditions SQD-FA05)

Third stage

(Diazomethyl)trimethylsilane (0.0125 ml, 0.025 mmol) was added to the solution of 2-[4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2 -[6-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenoxy]acetic acid (9 mg, 0.013 mmol) in benzene (0.13 ml)-methanol (0.08 ml) at room temperature and the mixture was stirred at room temperature for 1 hour. Formic acid (0.005 ml) was then added to the reaction mixture. the filtrate was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography (0.1% formic acid, acetonitrile/water) to obtain the title compound (8.3 mg, 90%) as a white amorphous solid.

LCMS: m/z 715[M+H] ⁺

HPLC retention time: 1.60 min (assay conditions QC-SMD-TFA05)

Example 151

(4aR)-1-[[2,3-Difluoro-4-(pyridin-4-ylmethoxy)phenyl]methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4 -hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 124

We used (4aR)-1-[(2,3-difluoro-4-hydroxyphenyl)methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4-hydroxy-4a-methyl -2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (example 325) and 4-(bromomethyl)pyridine hydrobromate and carried out operations similar to those used in example 146 to synthesize the desired connections.

LCMS: m/z 725[M+H] ⁺

HPLC retention time: 1.37 min (assay conditions QC-SMD-TFA05)

The phenolic derivatives of Examples 326, 327 and 330 and the alkyl bromide reagents, including those used in Comparative Examples 78 and 79, were used and operations similar to those used in the second step of Example 147 were performed to synthesize the compounds of the Examples described in the table below.

Although tautomers exist for some of the compounds described in this table, isomers may be observed in some cases but not others depending on the type of solvent used for the measurement. For example, ¹ H-NMR of Example 152 (chloroform-D) and Example 156 (dimethyl sulfoxide-D6) is as follows.

Example 152

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.43 (1H, s), 12.92 (1H, s), 9.61 (1H, s), 8.47 (1H, d, J=8.7 Hz), 7.95 (1H, s), 7.90 (1H, s), 7.79 (1H, d, J=8.7 Hz), 7.04 (1H, dd, J=8.1 , 8.1 Hz), 6.70 (1H, dd, J=8.1, 8.1 Hz), 4.98 (1H, d, J=14.3 Hz), 4.41 (1H, d , J=14.3 Hz), 4.07 (2H, t, J=6.2 Hz), 3.87 (1H, brs), 3.73-3.71 (1H, m), 3.66 -3.64 (1H, m), 3.56 (2H, m), 3.53-3.52 (2H, m), 3.33-3.31 (1H, m), 2.74 (1H , ddd, J=8.5, 8.5, 8.5 Hz), 2.55-2.53 (2H, m), 2.11 (1H, brs), 1.92-1.88 (2H , m), 1.82-1.77 (2H, m), 1.74-1.73 (1H, m), 1.68-1.62 (2H, m), 1.01 (2H, s ).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 18.16 (1H, s), 12.97 (1H, s), 9.59 (1H, s), 8.33 (1H, d, J=8.7 Hz) , 7.92 (2H, d, J=10.9 Hz), 7.79 (1H, d, J=8.4 Hz), 7.04 (1H, t, J=8.1 Hz), 6 .70 (1H, t, J=7.5 Hz), 5.01 (1H, d, J=17.3 Hz), 4.45 (1H, d, J=14.6 Hz), 4.07 (2H, t, J=6.2 Hz), 3.87 (1H, s), 3.72 (1H, d, J=10.7 Hz), 3.65 (1H, d, J=11, 9 Hz), 3.54 (4H, dt, J=19.0, 6.0 Hz), 3.26 (1H, s), 2.74 (1H, dd, J=16.6, 8.5 Hz), 2.63-2.61 (2H, m), 2.11 (1H, s), 1.92-1.88 (2H, m), 1.74-1.73 (2H, m) , 1.67-1.65 (2H, m), 1.50-1.47 (1H, m), 0.85 (3H, s).

Example 156

¹ H-NMR (DMSO-D ₆ ) δ: 15.77 (1H, brs), 12.17 (1H, brs), 9.71 (1H, s), 9.14 (1H, s), 8. 54 (1H, d, J=6.6 Hz), 8.16 (1H, d, J=8.1 Hz), 7.13 (1H, brs), 7.00 (1H, t, J=6.8 Hz), 4.99-4.17 (3H, m), 4.08 (2H, t, J=6.1 Hz), 3.59-3.54 (1H, m), 3.41-3 .24 (6H, m), 2.70 (1H, q, J=8.1 Hz), 2.41 (1H, brs), 1.79-1.48 (8H, m), 1.47- 1.31 (4H, m), 0.92 (3H, brs).

Example 157

(4aR)-1-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-H-[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 125

Triphenylphosphine (17.2 mg, 0.066 mmol), N-(2-hydroxyethyl)morpholine (7.5 mg, 0.057 mmol) and diethyl azodicarboxylate (0.03 ml, 0.065 mmol) were added to the (4aR)-1-[( 2,3-difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl] -6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 327) (10.6 mg, 0.016 mmol) in tetrahydrofuran (0.2 ml) and the mixture was stirred at room temperature in for 1.5 hours. The reaction mixture was then concentrated and the residue was purified by reverse phase column chromatography on silica gel to give the title compound (8.0 mg, 0.011 mmol) as a white solid. Using ¹ H-NMR and ¹³ C-NMR studies, it was confirmed that this solid contains 2 tautomers.

LCMS: m/z 757[M+H] ⁺

HPLC retention time: 1.30 min (SMD-TFA05)

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.44 (1H, s), 12.92 (1H, s), 9.61 (1H, d, J=1.0 Hz), 8.47 (1H, d, J=8.7 Hz), 7.95 (1H, d, J=1.0 Hz), 7.90 (1H, d, J=2.0 Hz), 7.79 (1H, dd, J=8.7, 2.0 Hz), 7.05 (1H, ddd, J=9.0, 6.8, 2.2 Hz), 6.71 (1H, ddd, J=9.0, 7.5, 1.2 Hz), 4.99 (1H, d, J=14.2 Hz), 4.40 (1H, d, J=14.2 Hz), 4.19 (2H, t, J=5.7 Hz), 3.74 (4H, t, J=4.6 Hz), 3.32 (1H, ddd, J=8.9, 8.9, 3.5 Hz), 2, 84 (2H, t, J=5.7 Hz), 2.74 (1H, ddd, J=8.9, 8.9, 8.9 Hz), 2.61-2.59 (4H, m) , 2.56-2.54 (1H, m), 1.76-1.73 (1H, m), 1.68-1.63 (2H, m), 1.00 (3H, s).

¹³ C-NMR (CDCl ₃ ) δ: 187.4 (qC), 169.8 (qC), 165.7 (qC), 162.5 (qC), 159.3 (CH), 156.6 (qC , J _CF =36.3 Hz), 150.3 (qC, J _CF =248.7, 10.5 Hz), 147.8 (qC, J _CF =5.5 Hz), 141.3 (qC, J _CF =247.9, 14.6 Hz), 138.7 (qC), 128.3 (CH, J _CF =3.3 Hz), 128.0 (qC), 127.1 (CH, J _CF =3.8 Hz), 127.0 (qC, J _CF =33.5 Hz), 125.1 (CH), 124.8 (CH), 123.6 (qC, J _CF =272.0 Hz) , 120.5 (qC, J _CF =275.4 Hz), 118.4 (qC, J _CF =12.7 Hz), 116.0 (CH, J _CF =2.5 Hz), 109.5 ( CH, J _CF =2.5 Hz), 93.6 (qC), 68.0 (CH ₂ ), 66.9 (CH ₂ ×2), 64.2 (qC), 57.5 (CH ₂ ) , 54.1 (CH ₂ ×2), 51.9 (CH ₂ ), 43.2 (CH ₂ ), 31.9 (CH ₂ ), 22.4 (CH ₃ ), 19.1 (CH ₂ ).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 18.17 (1H, s), 12.97 (1H, s), 9.59 (1H, s), 8.33 (1H, d, J=8.7 Hz), 7.93 (1H, s), 7.91 (1H, d, J=2.0 Hz), 7.79 (1H, dd, J=8.7, 2.0 Hz), 7, 05 (1H, ddd, J=9.0, 6.8, 2.2 Hz), 6.71 (1H, ddd, J=9.0, 7.5, 1.2 Hz), 5.02 ( 1H, d, J=14.5 Hz), 4.45 (1H, d, J=14.5 Hz), 4.19 (2H, t, J=5.7 Hz), 3.74 (4H, t, J=4.6 Hz), 3.25 (1H, ddd, J=8.8, 8.8, 3.2 Hz), 2.84 (2H, t, J=5.7 Hz), 2, 74 (1H, ddd, J=8.9, 8.9, 8.9 Hz), 2.61-2.59 (4H, m), 2.56-2.54 (1H, m), 1, 76-1.73 (1H, m), 1.68-1.63 (1H, m), 1.49-1.47 (1H, m), 0.84 (3H, s).

¹³ C-NMR (CDCl ₃ ) δ: 191.8 (qC), 170.2 (qC), 168.1 (qC), 165.5 (qC), 159.3 (CH), 156.6 (qC , J _CF =36.3 Hz), 150.3 (qC, J _CF =248.7, 10.5 Hz), 147.8 (qC, J _CF =5.5 Hz), 141.3 (qC, J _CF =247.9, 14.6 Hz), 138.7 (qC), 128.2 (CH, J _CF =3.3 Hz), 128.2 (qC), 127.1 (CH, J _CF =3.8 Hz), 127.0 (qC, J _CF =33.5 Hz), 125.1 (CH), 125.4 (CH), 123.6 (qC, J _CF =272.0 Hz) , 120.5 (qC, J _CF =275.4 Hz), 118.4 (qC, J _CF =12.7 Hz), 116.0 (CH, J _CF =2.5 Hz), 109.5 ( CH, J _CF =2.5 Hz), 84.3 (qC), 68.0 (CH ₂ ), 66.9 (CH ₂ ×2), 64.2 (qC), 57.5 (CH ₂ ) , 54.1 (CH ₂ ×2), 50.7 (CH ₂ ), 44.0 (CH ₂ ), 31.1 (CH ₂ ), 21.8 (CH ₃ ), 18.6 (CH ₂ ) .

The appropriate phenolic intermediates of Examples 324, 325, and 327 and suitable alcohol reagents were used and operations similar to those used in Example 156 were performed to synthesize the compounds of the Examples described in the table below.

Example 163

(4aR)-1-[[2,3-Difluoro-4-(2-morpholin-4-ylethylsulfanyl)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide hydrochloride

Formula 126

Cesium carbonate (67 mg, 0.206 mmol) was added to a solution of (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4- (trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 320) (30 mg, 0.04 mmol), palladium acetate (1.79 mg, 0.0080 mmol), triphenylphosphine (8.37 mg, 0.032 mmol) and triisopropylsilanethiol (9.87 mg, 0.052 mmol) in toluene (0.399 ml) and the mixture was stirred at 100°C for 2 hours and 45 minutes. Then further palladium acetate (1.79 mg, 0.0080 mmol), triisopropylsilanethiol (9.87 mg, 0.052 mmol) and 1,4-dioxane (0.4 ml) were added and the mixture was stirred at 110°C for 2 hours .

The reaction mixture was then cooled to room temperature, 4-(2-chloroethyl)morpholine hydrochloride (37.1 mg, 0.199 mmol) was added to this reaction mixture, and then the resulting mixture was heated at 100°C for several hours, then it was cooled to room temperature . This reaction mixture was purified using C18 reverse phase column chromatography. 4N was added to the resulting compound. hydrogen chloride/1,4-dioxane solution and the solution was concentrated and dried to give the title compound (17 mg, 53%) as a white solid.

LCMS: m/z 772 [M+H] ⁺

HPLC retention time: 1.35 min (assay conditions QC-SMD-TFA05)

Example 164

(4aR)-1-[[2,3-Difluoro-4-(morpholin-4-ylmethyl)phenyl]methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2 -[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide hydrochloride

Formula 127

First stage

Formula 128

A solution of potassium (bromomethyl)trifluoroborate (100 mg, 0.50 mmol), morpholine (45.7 mg, 0.525 mmol) and potassium carbonate (69.1 mg, 0.50 mmol) in tetrahydrofuran (0.50 ml) was heated at 80°C for 1 hour and then the resulting mixture was cooled to room temperature. The reaction mixture was then filtered and washed with acetone (15 ml), the solution was dried to give potassium trifluoro(morpholinomethyl)borate (68 mg, 66%) as the crude product.

Second stage

Palladium acetate (2.45 mg, 0.0109 mmol), dicyclohexyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (10.39 mg, 0.022 mmol) and cesium carbonate (89 mg, 0.272 mmol) was added twice to the solution of potassium trifluoro(morpholinomethyl)borate (28.2 mg, 0.136 mmol) obtained in the first step, and (4aR)-1-[(2,3-difluoro- 4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro -5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 320) (41 mg, 0.054 mmol) in a mixture of dioxane and water (0.495 ml and 0.0495 ml) and the mixture was heated and stirred at 80°C during the night. The reaction mixture was then cooled to room temperature, the reaction mixture was purified using reverse phase column chromatography. The resulting compound was dissolved in ethanol, then 4 N was added. the hydrogen chloride/dioxane solution and the resulting mixture were dried to obtain the title compound (28 mg, 68%) as a white solid.

LCMS: m/z 726 [M+H] ⁺

HPLC retention time: 1.28 min (assay conditions QC-SMD-TFA05)

Main tautomer

¹ H-NMR (CDCl ₃ ) δ: 13.60 (1H, s), 11.74 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=8.6 Hz), 7.95 (1H, dd, J=8.0, 1.8 Hz), 7.86 (1H, d, J=8.0 Hz), 7.75 ( 1H, m), 7.72 (1H, dd, J=8.6, 2.0 Hz), 7.54 (1H, d, J=1.8 Hz), 7.17 (1H, t, J =6.7 Hz), 4.86 (1H, d, J=14.9 Hz), 4.37-4.22 (4H, m), 3.97 (2H, dd, J=13.2, 2.6 Hz), 3.35 (2H, d, J=10.4 Hz), 3.27 (1H, dt, J=8.7, 3.2 Hz), 2.92 (2H, m) , 2.71 (1H, dd, J=16.7, 8.7 Hz), 2.60-2.51 (1H, m), 1.87-1.58 (4H, m), 1.04 (3H, s).

Minor tautomer

¹ H-NMR (CDCl ₃ ) δ: 11.91 (1H, s), 8.70 (1H, d, J=2.0 Hz), 8.17 (1H, d, J=8.6 Hz) , 7.80 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=2.0 Hz), 7.32 (1H, t, J=6.9 Hz), 5 .12 (1H, d, J=14.9 Hz), 4.48-4.38 (4H, m), 0.80 (3H, s).

Example 165

Methyl 4-[[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl] -6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-3,5-difluorobenzoate

Formula 129

Molybdenum hexacarbonyl (70.2 mg, 0.266 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (1:1 complex with dichloromethane) (4.4 mg, 0.0053 mmol) and 1,8-diazabicyclo [5.4.0]undec-7-ene (0.0024 ml, 0.159 mmol) was added to the solution of (4aR)-1-[(2,6-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl -2-oxo-X-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3 -carboxamide (Example 322) (40 mg, 0.053 mmol) in methanol (2 ml) and the mixture was stirred under nitrogen at 70°C for 4 hours. The reaction mixture was added to 1 N. hydrochloric acid, the resulting mixture was extracted with dichloromethane and then the organic layer was dried over anhydrous magnesium sulfate, the resulting mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (hexane:ethyl acetate = 2:1) to give the title compound (29.3 mg, 81%) as a light brown oil.

LCMS: m/z 685 [M+H] ⁺

HPLC retention time: 1.68 min (assay conditions QC-SMD-TFA05)

Comparative Example 80

(4aR)-N-(4-Bromo-3,5-difluorophenyl)-4-hydroxy-4a-methyl-2-oxo-1,5,6,7-tetrahydropyrrolo[1,2-b]pyridazin-3- carboxamide

Formula 130

First stage

Formula 131

A solution of 4-bromo-3,5-difluoroaniline (2.00 g, 9.62 mmol) and Meldrum acid (2.77 g, 19.2 mmol) in toluene (18 ml) was stirred at 90 °C for 3 h Then the reaction mixture was cooled to 0°C, and the precipitate was collected by filtration. The resulting solid was purified by reverse phase column chromatography (0.1% formic acid-water/acetonitrile) to give 3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate (2.00 g , 71%) in the form of a white powdery substance.

LCMS: m/z 294 [M+H] ⁺

HPLC retention time: 0.66 min (assay conditions SQD-FA05)

Second stage

Formula 132

We used 2,4-dimethoxybenzaldehyde methyl ester hydrochloride, (I)-2-methylpyrrolidine-2-carboxylic acid, and 3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate and performed operations similar to those used in comparative example 1-1, for the synthesis of (4aR)-N-(4-bromo-3,5-difluorophenyl)-1-[(2,4-(dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2 -oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide.

LCMS: m/z 554 [M+H] ⁺

HPLC retention time: 1.64 min (assay conditions SQD-FA05)

Third stage

(4aR)-N-(4-Bromo-3,5-difluorophenyl)-1-[(2,4-(dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro- 5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (910 mg, 1.65 mmol) and triisopropylsilane (0.68 ml, 3.29 mmol) were dissolved in trifluoroacetic acid (6 ml) and after cooling the mixture to Trifluoromethanesulfonic acid (0.15 mL, 1.65 mmol) was added dropwise at 0° C. After stirring the mixture at room temperature for 30 min, the reaction mixture was added to ice-cooled water (50 mL), neutralized with potassium carbonate (5.5 g, 39.8 mmol) and extracted three times with ethyl acetate (100 ml). The organic layer was then washed with brine, the resulting mixture was dried over sodium sulfate. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified using C18 reverse phase column chromatography (0.1% formic acid-water/acetonitrile) to obtain the title compound (590 mg, 89%) as a white solid.

LCMS: m/z 402 [M+H] ⁺

HPLC retention time: 0.70 min (assay conditions SQD-FA05)

Comparative Example 81

(4aR)-4-Hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-1,5,6,7- tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 133

First stage

Formula 134

4-(Trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Comparative Example 42) (2.0 g) was dissolved in tetrahydrofuran (30 ml), potassium triphosphate (4.16 g) was added and the mixture was stirred at room temperature for 3 minutes. Methyl 3-chloro-3-oxopropanoate (1.40 ml) was added and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate (100 ml) and water (100 ml) were added to separate and the organic layer was washed with 12% brine and concentrated under reduced pressure to give 3-O-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridine-3 -yl]phenyl]-1-O-methyl ester of propanedicarboxylic acid as a crude product.

LCMS: m/z 407 [M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Second stage

Formula 135

Methanol (20 ml) and 10 N. aqueous sodium hydroxide solution (1.96 ml) was added to 3-0-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl] 1-O-methyl ether obtained in the first step , and the mixture was stirred at room temperature for 10 hours 6 N. Hydrochloric acid was added until pH=3, ethyl acetate and water were added to separate, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane (90 ml) and ethyl acetate (10 ml) were added to the resulting residue, the mixture was stirred and then filtered, and the resulting solid was dried to give 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl) pyridin-3-yl)phenyl)amino)propanoate (2.34 g, yield in 2 stages 91%).

LCMS: m/z 393 [M+H] ⁺

HPLC retention time: 0.29 min (SQD-FA50 assay conditions)

Third stage

Formula 136

(R)-2-Methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (8.4 g, 46.8 mmol) was suspended in dichloromethane (50 ml), p-toluenesulfonic acid monohydrate (9.34 g, 49.1 mmol) was added ) and the mixture was stirred under a nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, toluene was added to azeotrope it, then the residue was suspended in dichloromethane (50 ml), sodium nitrite (3.55 g, 69.0 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to obtain (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The resulting crude product was dissolved in acetic acid (200 ml) and methanol (30 ml), powdered zinc (29.4 g, 4501 mmol) was added in separate portions under a stream of nitrogen at 0°C and the mixture was stirred for 1 hour. To the reaction mixture methanol (100 ml) was added, the mixture was filtered through a pad of celite and then the filtrate was concentrated under reduced pressure. The same operation was then repeated twice, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol). Then 4 N was added to the resulting fraction. hydrogen chloride/1,4-dioxane solution, the filtrate was concentrated under reduced pressure to give (R)-1-amino-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (6.4 g, 70%).

LCMS: m/z 158.9 [M+H] ⁺

HPLC retention time: 0.33 min (assay conditions SMD-TFA05)

Fourth stage

Formula 137

Methyl ester (R)-2-methyl-1-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2 -carboxylic acid and (R)-1-amino-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride were used as the reagent and starting material, respectively, and operations similar to those used in the second step of Comparative Example 1-1 were performed to synthesize the methyl ester (R)-2-methyl-1-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2-carboxylic acids.

LCMS: m/z 531 [M-H] ^-

HPLC retention time: 0.88 min (SQD-FA05)

Fifth stage

We used methyl ester (R)-2-methyl-1-(3-oxo-3-((4-(trifluoromethyl) 2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2 - carboxylic acid and carried out operations similar to those used in the third stage of comparative example 1-1 to synthesize the desired compound.

LCMS: m/z 501 [M+H] ⁺

HPLC retention time: 1.03 min (SQD-FA05)

Comparative Example 82

(4aR)-4-Hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-1,5,6,7, -tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 138

First stage

Formula 139

4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Comparative Example 50) and Meldrum's acid were used and operations similar to those used in the second step of Comparative Example 80 were performed to synthesize 3-oxo-3 -((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoate.

Second stage

We used (R)-1-amino-2-methylpyrrolidin-2-carboxylic acid methyl ester hydrochloride and 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl )amino)propanoate and carried out operations similar to those used in the fourth and fifth steps of comparative example 81 to synthesize the desired compound.

LCMS: m/z 502 [M+H] ⁺

HPLC retention time: 1.02 min (SQD-FA05)

Example 166

(4aR)-N-(4-Bromo-3,5-difluorophenyl)-1-[(4-bromo-2-fluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro -5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 140

1.7 n. A solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (14.7 mg, 0.055 mmol) in toluene (0.0644 ml, 0.109 mmol) and potassium 2,2-dimethylpropan-1-olate were added to the solution (4aR )-N-(4-6poM-3,5-difluorophenyl)-4-hydroxy-4a-methyl-2-oxo-1,5,6,7-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide ( comparative example 80) (20.0 mg, 0.050 mmol) in N,N-dimethylformamide (0.249 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was immediately purified by C18 reverse phase column chromatography (0.1% formic acid-acetonitrile/water) to give the title compound (6.0 mg, 20%) as an off-white amorphous solid.

LCMS: m/z 588 [M-H] ^-

HPLC retention time: 1.32 min (SQD-FA05)

The appropriate pyridazinone intermediates of Comparative Examples 80-82 were used and suitable benzyl halide reagents and operations similar to those used in Example 166 were performed to synthesize the compounds of the Examples described in the table below.

The corresponding compounds described in this table include their tautomers. For example, ¹ H-NMR of example 196 is as follows.

Main tautomer

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 16.40 (1H, s), 12.00 (1H, s), 7.40-7.28 (4H, m), 7.11-7, 04 (1H, m), 5.14 (1H, d, J=14.1 Hz), 4.47 (1H, d, J=14.1 Hz), 3.37-3.32 (1H, m ), 2.82-2.76 (1H, m), 2.61-2.54 (1H, m), 1.76-1.61 (3H, m), 1.01 (3H, s).

Minor tautomer

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 16.40 (1H, s), 12.18 (1H, s), 7.40-7.28 (4H, m), 7.11-7, 04 (1H, m), 5.11 (1H, d, J=14.4 Hz), 4.53 (1H, d, J=14.4 Hz), 3.32-3.26 (1H, m ), 2.84-2.77 (1H, m), 2.65-2.61 (1H, m), 1.81-1.70 (3H, m), 0.88 (3H, s).

Example 234

(4aR)-4-Hydroxy-4a-methyl-2-oxo-1-(4,4,4-trifluorobutyl)-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl ]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 141

We used methyl-(4aR)-1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 3-carboxylate (Comparative Example 12) and 1,1,1-trifluoro-4-iodobutane and sequentially carried out operations similar to those used in the third step of Comparative Example 80, Example 166 and Example 21, and obtained the desired compound.

LCMS: m/z 612 [M+H] ⁺

HPLC retention time: 1.63 min (assay conditions SMD-TFA05)

Example 235

Ethyl 7-[(4aR)-4-hydroxy-4a-methyl-2-oxo-3-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]carbamoyl]- 6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]heptanoate

Formula 142

We used methyl-(4aR)-1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin- 3-carboxylate (Comparative Example 12) and ethyl 7-bromoheptanoate and carried out operations similar to those used in Example 234 to obtain the title compound.

LCMS: m/z 657 [M+H] ⁺

HPLC retention time: 1.70 min (assay conditions QC-SMD-TFA05)

Example 236

(4aR)-4-Hydroxy-1-[8-[2-(2-methoxyethoxy)ethoxy]octyl]-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 143

First stage

Formula 144

Sodium iodide was added to a solution of 1-bromo-8-(2-(2-methoxyethoxy)ethoxy)octane (1.00 g, 3.21 mmol) in acetone and the mixture was stirred at 60°C for 2 hours. The reaction mixture was then cooled to room temperature, the precipitate was filtered for separation and then the filtrate was washed with sodium thiosulfate and brine, the resulting mixture was dried over sodium sulfate. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 1-iodo-8-(2-(2-methoxyethoxy)ethoxy)octane (1.05 g, 91%) as a yellow oil.

Second stage

Methyl-(4aR)-1-[(2,4-(dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine was used -3-carboxylate (Comparative Example 12) and the iodine-containing derivative obtained in the first step, and operations similar to those used in Example 234 were performed to obtain the desired compound.

LCMS: m/z 732 [M+H] ⁺

HPLC retention time: 1.76 min (assay conditions QC-SMD-TFA05)

Example 237

(3S)-3-Tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy -2-methyl-6-oxo-3H-pyrimidine-5-carboxamide

First stage

Methyl-(2S)-3,3-Dimethyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoate

Formula 145

(S)-2-((T-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (11.3 g, 48.9 mmol) was dissolved in N,N-dimethylformamide (114 ml), silver oxide (34, 0 g, 147 mmol) and iodomethane (18.3 ml, 294 mmol) and the mixture was stirred under nitrogen at 45°C overnight. The reaction mixture was diluted with ethyl acetate (200 ml) and filtered, water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.7 g, 100%).

¹ H-NMR (CDCl ₃ ) δ: 4.75 (1H, s), 3.71 (3H, s), 2.94 (3H, s), 1.48 (9H, s), 1.08 ( 9Н, s).

Second stage

Methyl-(S)-3,3-dimethyl-2-(methylamino)butanoate hydrochloride

Formula 146

Hydrochloric acid (dioxane solution, 122 ml, 489 mmol) was added to methyl ((2S)-3,3-dimethyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoate (12 .69 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (9.58 g, 100%).

¹ H-NMR (DMSO-D ₆ ) δ: 9.00 (1H, brs), 3.89-3.86 (1H, m), 3.79 (3H, s), 2.54 (3H, s ), 1.02 (9H, s).

Third stage

Methyl (2S)-2-[[(2,3-difluorophenyl)methylidenamino]-methylamino]-3,3-dimethylbutanoate

Formula 147

Methyl (S)-3,3-Dimethyl-2-(methylamino)butanoate hydrochloride (70.0 mg, 0.358 mmol) was dissolved in acetic acid (3.58 mmol, 205 μl) and water (716 μl), at 0 °C, sodium nitrite (33.4 mg, 0.393 mmol) was added and the mixture was stirred under nitrogen for 1 hour. Zinc (19.7 g, 302 mmol) was added to the reaction mixture at 0 °C and the mixture was stirred under nitrogen at for 4 hours. The reaction mixture was then filtered, methanol (3.58 ml) and 2,3-difluorobenzaldehyde (39.1 µl, 0.358 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate and brine, and then the resulting mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate). and the desired compound was obtained (44.2 mg, 41%).

LCMS: m/z 299 [M+H] ⁺

HPLC retention time: 1.13 min (assay conditions SQD-AA05)

Fourth stage

2-Methylpropyl ester (3S)-3-tert-butyl-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyrimidine-5-carboxylic acid

Formula 148

Methyl ((2S)-2-[[(2,3-difluorophenyl)methylideneamino]-methylamino]-3,3-dimethylbutanoate (44.2 mg, 0.148 mmol)) was dissolved in hydrochloric acid (methanol solution, 442 μl ), borane-pyridine (29.9 μl, 0.296 mmol) was added at 0°C and the mixture was stirred under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate, the organic layer was washed with 1 N. dipotassium hydrogen phosphate aqueous solution and brine, and the aqueous layer was separated using a phase separator and concentrated under reduced pressure to obtain methyl (2S)-2-[[(2,3-difluorophenyl)methylamino]-methylamino]-3,3-dimethylbutanoate as a crude product. The resulting crude product was dissolved in ethyl acetate (750 μl) and then 3-isobutoxy-3-oxopropanoate (0.026 g, 0.163 mmol), pyridine (35.8 μl, 0.444 mmol) and 2,4,6-tripropyl were added at 0° C. -1,3,5,2,4,6-trioxatriphosphinan-2,4,6-trioxide (ethyl acetate solution, 174 µl, 0.296 mmol) and the mixture was stirred under nitrogen atmosphere for 1 hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 N. aqueous dipotassium hydrogen phosphate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl (2S)-2-[[(2,3-difluorophenyl)methyl-[3-(2-methylpropoxy)-3-oxopropanoyl ]amino]-methylamino]-3,3-dimethylbutanoate as a crude product. The resulting crude product was dissolved in N,N-dimethylformamide (750 µl), cesium carbonate (121 mg, 0.370 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 80°C for 2 hours. Dichloromethane and 1 N were added to the reaction mixture. hydrochloric acid at 0°C and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified using C18 reverse phase column chromatography (acetonitrile/water) to give the title compound (48.1 mg, 79%).

LCMS: m/z 411.5 [M+H] ⁺

HPLC retention time: 1.03 min (assay conditions SQD-AA05)

Fifth stage

(3S)-3-Tert-butyl-N-[4-chloro-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-1-[(2,3-difluorophenyl)methyl]-4-hydroxy -2-methyl-6-oxo-3H-pyrimidine-5-carboxamide

Formula 149

2-Methylpropyl ester (3S)-3-tert-butyl-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxylic acid (6, 3 mg, 0.015 mmol) was dissolved in toluene (200 μl), 4-chloro-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Comparative Example 53) (4.2 mg, 0.015 mmol) was added and the mixture heated for 1 hour. The reaction mixture was concentrated and the resulting residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to give the title compound (8.0 mg, 85%).

LCMS: m/z 610.3 [M+H] ⁺

HPLC retention time: 1.72 min (assay conditions QC-SMD-TFA05)

Comparative Example 83

Methyl-(S)-2-(ethylamino)-3,3-dimethylbutanoate hydrochloride

First stage

Methyl (2S)-2-[benzyl(ethyl)amino]-3,3-dimethylbutanoate

Methyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (5.27 g, 29.0 mmol) was suspended in dichloroethane (250 ml) and then benzaldehyde (2.93 ml, 29.0 mmol) and triacetoxyhydroborate were added sodium (12.3 g, 58.0 mmol) and the mixture was stirred under nitrogen at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and filtered, water was added and the resulting mixture was extracted with ethyl acetate. A saturated sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (2S)-2-(benzylamino)-3,3-dimethylbutanoate methyl ester (6.82 g) as a crude product. A portion of the resulting crude product (2.00 g, 8.50 mmol) was dissolved in dichloromethane (42.5 ml), acetaldehyde (2.39 ml, 42.5 mmol) and sodium triacetoxyhydroborate (3.60 g, 17.0) were added mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 24 hours. A saturated sodium bicarbonate solution was added to the reaction mixture at 0°C and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.65 g, 88%).

LCMS: m/z 264.3 [M+H] ⁺

HPLC retention time: 1.14 min (assay conditions SMD-TFA05)

Second stage

Methyl-(S)-3,3-dimethyl-2-(methylamino)butanoate hydrochloride

Methyl (2S)-2-[benzyl(ethyl)amino]-3,3-dimethylbutanoate (1.64 g, 6.23 mmol) was dissolved in ethyl acetate (6.23 ml), palladium hydroxide on carbon (20 wt. %, 328 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered, hydrochloric acid (dioxane solution, 4.67 ml, 18.7 mmol) was added and then the filtrate was concentrated under reduced pressure and the desired compound was obtained (922 mg, 71%).

¹ H-NMR (DMSO-D ₆ ) δ: 8.98 (1H, brs), 8.76 (1H, brs), 3.88 (1H, d, J=10.0 Hz), 3.78 ( 3H, s), 2.94 (2H, q, J=6.0 Hz), 1.22 (3H, t, J=7.3 Hz), 1.04 (9H, s).

Comparative Example 84

Methyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoate

Methyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (1.00 g, 5.50 mmol) was suspended in tetrahydrofuran (250 ml) and then trifluoromethanesulfonic acid 2,2,2-trifluoroethyl (1.59 ml) was added , 11.0 mmol) and diisopropylethylamine (4.79 ml, 27.5 mmol) and the mixture was stirred under a nitrogen atmosphere at 60°C for 27 hours. The mixture was then cooled to room temperature, the reaction mixture was filtered, concentrated, hydrochloric acid was added, the filtrate was concentrated under reduced pressure and the resulting residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to obtain the title compound as a solution in acetonitrile/water.

LCMS: m/z 228.3[M+H] ⁺

HPLC retention time: 1.19 min (assay conditions SMD-TFA05)

Comparative Example 85

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride

First stage

Methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutanecarboxylate

1-((tert-Butoxycarbonyl)amino)cyclobutanecarboxylic acid (1.00 g, 4.65 mmol) was dissolved in N,N-dimethylformamide (9.29 ml) and then sodium hydride (55%, 0 .61 g, 13.9 mmol) and methyl iodide (1.45 ml, 23.3 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours. 1 N was added to the reaction mixture at 0°C. an aqueous hydrochloric acid solution and the mixture was extracted with diethyl ether. The organic layer was washed with water, saturated sodium bicarbonate solution, 10 wt. % aqueous sodium thiosulfate solution and brine, the aqueous layer was separated using a phase separator, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.13 g, 100% ).

LCMS: m/z 266.3 [M+Na] ⁺

HPLC retention time: 0.92 min (assay conditions SQD-AA05)

Second stage

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride

Using a procedure similar to that used in the second step of Example 237, the desired compound was synthesized from methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutanecarboxylate.

¹ H-NMR (DMSO-D ₆ ) δ: 9.97 (2H, brs), 3.86 (3H, s), 2.60-2.57 (2H, m), 2.50-2.46 (5H, m), 2.06-2.03 (2H, m).

Comparative Example 86

Methyl 1-(methylamino)cyclobutanecarboxylate-4-toluenesulfonate

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride (1.39 g, 7.75 mmol) was dissolved in ethyl acetate (15 ml) and then 4-toluenesulfonate monohydrate (1.47 g, 7.75 mmol) was added and the mixture was concentrated under reduced pressure , ethyl acetate (15 ml) was added and the resulting mixture was filtered to obtain the title compound (1.96 g, 80%).

¹ H-NMR (DMSO-D ₆ ) δ: 9.10 (2H, brs), 7.48 (2H, d, J=7.9 Hz), 7.12 (2H, d, J=7.9 Hz), 3.82 (3H, s), 2.56-2.31 (7H, m), 2.29 (3H, s), 2.05-1.99 (2H, m).

Comparative Example 87

Methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride

Using a procedure similar to that used in the first and second steps of Comparative Example 85, the title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid.

¹ H-NMR (DMSO-D ₆ ) δ: 9.71 (2H, brs), 3.79 (3H, s), 3.34 (3H, s), 2.20-2.13 (2H, m ), 2.05-1.98 (2H, m), 1.89-1.86 (2H, m), 1.74-1.71 (2H, m).

Comparative Example 88

Methyl 1-(methylamino)cyclopentanecarboxylate 4-toluenesulfonate

Methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride (1.50 g, 7.75 mmol) was dissolved in ethyl acetate (15 ml) and then 4-toluenesulfonate monohydrate (1.47 g, 7.75 mmol) was added and the mixture was concentrated under reduced pressure , ethyl acetate (15 ml) was added and the resulting mixture was filtered to obtain the title compound (2.00 g, 78%).

¹ H-NMR (DMSO-D ₆ ) δ: 9.18 (2H, brs), 7.48 (2H, d, J=7.9 Hz), 7.11 (2H, d, J=7.9 Hz), 3.79 (3H, s), 2.57 (3H, brs), 2.29 (3H, s), 2.24-2.10 (2H, m), 1.99-1.86 (2H, m), 1.86-1.65 (2H, m).

Comparative Example 89

Methyl 1-(methylamino)cyclohexanecarboxylate hydrochloride

Using a procedure similar to that used in the first and second steps of Comparative Example 85, the title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid.

¹ H-NMR (DMSO-D ₆ ) δ: 9.43 (2H, brs), 3.84 (3H, s), 2.51 (3H, s), 2.15-2.12 (2H, m ), 1.77-1.73 (4H, m), 1.58-1.55 (1H, m), 1.47-1.44 (2H, m), 1.35-1.29 (1H , m).

LCMS: m/z 172.5 [M+H] ⁺

HPLC retention time: 0.52 min (assay conditions SMD-TFA05)

Comparative Example 90

Methyl 2-ethyl-2-(methylamino)butanoate hydrochloride

First stage

2-(((benzyloxy)carbonyl)amino)-2-ethylbutanoate methyl ester

2-Ethyl-2-(methoxycarbonyl)butanoate (307.0 mg, 1.76 mmol) was dissolved in toluene (11.7 mL) and then triethylamine (295 μL, 2.12 mmol) and diphenylphosphoryl azide (458 μL, 2 .12 mmol) and the mixture was stirred at room temperature for 1.5 h and at 95°C for 0.5 h. Benzyl alcohol (1.1 ml, 10.6 mmol) was added and the mixture was stirred at 95°C in during the night. The reaction mixture was concentrated under reduced pressure, diluted with diethyl ether and the resulting mixture was washed with 1 N. hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (488.1 mg, 99%).

LCMS: m/z 280[M+H] ⁺

HPLC retention time: 1.11 min (assay conditions SMD-TFA05)

Second stage

Methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-2-ethylbutanoate

A solution of methyl 2-(((benzyloxy)carbonyl)amino)-2-ethylbutanoate (481.3 mg, 1.72 mmol) in N,N-dimethylformamide (3.4 ml) was then added to the sodium hydride at 0°C (83 mg, 3.45 mmol), methyl iodide (269 μl, 4.31 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1 N. hydrochloric acid, water, saturated sodium bicarbonate solution, aqueous sodium thiosulfate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (438.5 mg, 87%).

LCMS: m/z 294[M+H] ⁺

HPLC retention time: 1.14 min (assay conditions SMD-TFA05)

Third stage

Methyl 2-ethyl-2-(methylamino)butanoate hydrochloride

Palladium on carbon (10 wt.%, 15.8 mg) was added to a solution of methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-2-ethylbutanoate (434.5 mg, 1.48 mmol) in methanol (7.4 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. A methanolic hydrochloric acid solution (0.5 M, 14.8 ml) was added to the reaction mixture, and the resulting mixture was filtered and concentrated under reduced pressure to obtain the desired compound (281.9 mg, 97%).

¹ H-NMR (CD ₃ OD) δ: 3.92 (3H, s), 3.34 (1H, m), 2.69 (3H, s), 2.04 (4H, m), 0.99 (6H, t).

LCMS: m/z 160[M+H] ⁺

HPLC retention time: 0.49 min (assay conditions SMD-TFA05)

Comparative Example 91

4-Chloro-5-methyl-6-(trifluoromethyl)pyrimidine

First stage

5-Methyl-6-(trifluoromethyl)pyrimidin-4(3H)-one

Ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (200 mg, 1.01 mmol) and formamidine hydrochloride (122 mg, 1.51 mmol) were dissolved in ethanol (2.0 ml) and the mixture was stirred at room temperature for 2 hours. Sodium ethoxide (172 mg, 2.52 mmol) was added and the mixture was stirred at 80°C for 4 hours. 1 N was added to the reaction mixture. hydrochloric acid and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was washed with diethyl ether to obtain the title compound (158 mg, 88%).

LCMS: m/z 179[M+H] ⁺

HPLC retention time: 0.46 min (assay conditions SQD-FA05)

Second stage

4-Chloro-5-methyl-6-(trifluoromethyl)pyrimidine

Phosphoryl chloride (1.06 ml, 11.4 mmol) was added to 5-methyl-6-(trifluoromethyl)pyrimidin-4(3H)-one (135 mg, 0.758 mmol) and the mixture was stirred at 100°C for 1 hour. A saturated sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a crude product.

LCMS: m/z 197[M+H] ⁺

HPLC retention time: 0.95 min (assay conditions SMD-TFA05)

Comparative Example 92

4,5-Dichloro-6-(trifluoromethyl)pyrimidine

First stage

5-Chloro-6-(trifluoromethyl)pyrimidin-4(3H)-one

6-(Trifluoromethyl)pyrimidin-4(3H)-one (1.0 g, 6.1 mmol) and N-chlorosuccinimide (1.1 g, 7.9 mmol) were dissolved in N,N-dimethylformamide (5.0 ml) and the mixture was stirred at 50°C for 9 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography (water/acetonitrile, 0.1% formic acid) to give the title compound (368.5 mg, 31%).

LCMS: m/z 199[M+H] ⁺

HPLC retention time: 0.68 min (assay conditions SMD-TFA05)

Second stage

4,5-Dichloro-6-(trifluoromethyl)pyrimidine

Phosphoryl chloride (1.4 ml, 15.1 mmol) was added to 5-chloro-6-(trifluoromethyl)pyrimidin-4(3H)-one (150.0 mg, 0.756 mmol) and the mixture was stirred at 100°C for 1 After 5 hours, ice water was added to the reaction mixture and extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (121.5 mg) as a crude product.

LCMS: m/z 217[M+H] ⁺

HPLC retention time: 1.03 min (assay conditions SMD-TFA05)

Comparative Example 93

4-Chloro-2-(6-chloropyrimidin-4-yl)aniline

Dioxane (9.6 ml) was added to 2-amino-4-chlorophenylboronic acid pinacoline ester (608 mg, 2.4 mmol), 4,6-dichloropyridine (892 mg, 6.0 mmol), tetrakis(triphenylphosphine) palladium ( 138 mg, 0.12 mmol) and potassium phosphate (2.03 g, 9.6 mmol) and the mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate.

The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (349.6 mg, 59%).

LCMS: m/z 240[M+H] ⁺

HPLC retention time: 1.14 min (assay conditions SMD-TFA05)

The boronic acid derivatives and halides described in the table below were used to synthesize the aniline intermediates described in the table below by performing operations similar to those used in Comparative Example 93

Comparative Example 99

6-(2-Amino-5-chlorophenyl)pyrimidine-4-carbonitrile

4-chloro-2-(6-chloropyrimidin-4-yl)aniline was used and operations similar to those used in Comparative Example 63 were performed to synthesize the title compound.

LCMS: m/z 265[M+H] ⁺

HPLC retention time: 1.16 min (assay conditions SMD-TFA05)

Comparative Example 100

6-(2-Amino-5-chlorophenyl)-5-methylpyrimidine-4-carbonitrile

4-chloro-2-(6-chloropyrimidin-4-yl)aniline was used and operations similar to those used in Comparative Example 63 were performed to synthesize the title compound.

LCMS: m/z 245[M+H] ⁺

HPLC retention time: 0.75 min (assay conditions SQD-FA05)

Examples 238-300

Suitable aniline reagents of Comparative Examples 94-100 described in Table 30, suitable benzaldehyde derivatives of Comparative Example 3 known in the literature or commercially available, and suitable amines of Comparative Examples 85-90 known in the literature or commercially available were used to synthesize the compounds described in the table below, by performing operations similar to those used in the third through fifth stages of Example 237.

Purification conditions: HPLC

Mobile phase: MeCN/water (no additive), MeCN/water (0.1% formic acid), MeCN/water (0.1% NEt ₃ ) or CHCl ₃

Column:

YMC-Actus ODS-A (100×20 mm ID (inner diameter), S - 5 µm, 12 nm)

YMC-Actus Triart C18 (100×30 mm ID, S - 5 µm, 12 nm)

YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

JAI JAIGEL-H (600×20 mm ID, GPC)

Comparative Example 101

Methyl 2-(2,3-difluorobenzyl)-5-hydroxy-6,6-dimethyl-3-oxo-1-phenyl-1,2,3,6-tetrahydropyridazine-4-carboxylate

First stage

Phenylhydrazine (0.76 g, 7.1 mmol) and ethyl 2-bromo-2-methylpropionate (1.93 g, 9.9 mmol) were dissolved in N,N-diisopropylethylamine (1.00 g, 7.8 mmol ) and the mixture was stirred and heated under nitrogen at 110°C for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Methanol (6 ml) and 2,3-difluorobenzaldehyde (0.77 ml, 7.1 mmol) were added to the resulting crude product, and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue Purified by C18 reverse phase column chromatography on silica gel (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give ethyl 2-(2-(2,3-difluorobenzylidene)-1-phenylhydrazinyl )-2-methylpropanoate (0.51 g, 21%) as a yellow oil.

LCMS: m/z 347[M+H] ⁺

HPLC retention time: 1.12 min (assay conditions SQD-FA05)

Second stage

Ethyl 2-(2-(2,3-difluorobenzylidene)-1-phenylhydrazinyl)-2-methylpropanoate obtained in the first step was used and operations similar to those used in Comparative Example 1-2 were performed to obtain the desired compound (0.38 g, 65%) as a yellow oil.

LCMS: m/z 403[M+H] ⁺

HPLC retention time: 0.97 min (assay conditions SQD-FA05)

Comparative Example 102

Methyl 6-(2,3-difluorobenzyl)-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylate

First stage

Methylhydrazine (0.10 g, 2.17 mmol) and ethyl 1-bromocyclobutanecarboxylate (0.23 g, 1.1 mmol) were dissolved in N,N-diisopropylethylamine (0.30 g, 2.3 mmol) and the mixture was stirred and heated under nitrogen atmosphere at 110°C for 15 hours. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The resulting crude product was added to the reaction mixture, and then methanol (2 ml) and 2,3-difluorobenzaldehyde (0.12 ml, 1.1 mmol) were added and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at under reduced pressure and the resulting residue was purified by C18 reverse phase column chromatography on silica gel (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give ethyl 1-(2-(2,3-difluorobenzylidene )-1-methylhydrazinyl)cyclobutanecarboxylate (36 mg, 11%) as a colorless oil.

LCMS: m/z 297[M+H] ⁺

HPLC retention time: 1.15 min (assay conditions SQD-FA05)

Second stage

Ethyl 1-(2-(2,3-difluorobenzylidene)-1-methylhydrazinyl)cyclobutanecarboxylate obtained in the first step was used and operations similar to those used in the second step of Comparative Example 101 were performed to obtain the title compound (50 mg, 78% ) in the form of red oil.

LCMS: m/z 353[M+H] ⁺

HPLC retention time: 0.93 min (assay conditions SQD-FA05)

Comparative Example 103

Methyl 2-(2,3-difluorobenzyl)-5-hydroxy-1,6,6-trimethyl-3-oxo-1,2,3,6-tetrahydropyridazine-4-carboxylate

First stage

Methylhydrazine (0.46 g, 10.0 mmol) and ethyl 2-bromo-2-methylpropionate (1.07 g, 5.5 mmol) were dissolved in tetrahydrofuran (5.0 ml) and then N,N-diisopropylethylamine was added (0.84 g, 6.5 mmol) and the mixture was stirred and heated under a nitrogen atmosphere at 60°C for 66 hours. The reaction mixture was then cooled to room temperature, methanol (60 ml) and 2,3- difluorobenzaldehyde (0.55 ml, 5.0 mmol) and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by C18 reverse phase column chromatography on silica gel (0.1 % formic acid-water/0.1% formic acid-acetonitrile) to obtain ethyl 2-[2-(2,3-difluorobenzylidene)-1-methylhydrazinyl]-2-methylpropionate (0.8 g, 56%) in in the form of a colorless oil.

LCMS: m/z 285[M+H] ⁺

HPLC retention time: 1.00 min (assay conditions SQD-FA05)

Second stage

Ethyl 2-[2-(2,3-difluorobenzylidene)-1-methylhydrazinyl]-2-methylpropionate obtained in the first step was used and operations similar to those used in the second step of Comparative Example 101 were performed to obtain the title compound (650 mg, 68%) as a yellow oil.

LCMS: m/z 341[M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Suitable aniline reagents and suitable ester intermediates of Comparative Examples 101-103 were used to synthesize the compounds described in the table below using operations similar to those used in the fifth step of Example 237.

Example 313

2-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-5-hydroxy-1,6,6-trimethyl-3-oxo-N-[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]pyridazine-4-carboxamide

First stage

Methylhydrazine, ethyl 2-bromo-2-methylpropionate and the aldehyde reagent synthesized in Comparative Example 3 were used and operations similar to those used in the first step of Comparative Example 103 were performed to obtain ethyl 2-(2-(2,3-difluoro) -4-(2-morpholinoethoxy)benzylidene)-1-methylhydrazinyl)-2-methylpropanoate.

LCMS: m/z 414[M+H] ⁺

HPLC retention time: 0.96 min (assay conditions SMD-TFA05)

Second stage

Ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzylidene)-1-methylhydrazinyl)-2-methylpropanoate (50 mg, 0.12 mmol) obtained in the first step was dissolved in 10 % methanolic hydrochloric acid solution (1.8 ml), borane-pyridine (28 mg, 0.30 mmol) was added at 0°C and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 1 N was added. an aqueous dipotassium hydrogen phosphate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)- 2-methylpropanoate as crude product.

LCMS: m/z 416[M+H] ⁺

HPLC retention time: 0.63 min (assay conditions SMD-TFA05)

Third stage

The crude product, ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)-2-methylpropanoate, obtained in the second step, was dissolved in ethyl acetate (800 μl) and then at 0°C, the reagent carboxylic acid synthesized in the first stage of comparative example 82, pyridine (20 μl, 0.242 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan-2 were added ,4,6-trioxide (ethyl acetate solution, 92 μl, 0.145 mmol) and the mixture was stirred under nitrogen overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methyl-2- (3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoyl)hydrazinyl)-2-methylpropanoate as crude product.

LCMS: m/z 791[M+H] ⁺

HPLC retention time: 1.19 min (assay conditions SMD-TFA05)

Fourth stage

We used ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methyl-2-(3-oxo-3-((4-(trifluoromethyl)-2-(6 -(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoyl)hydrazinyl)-2-methylpropanoate obtained in the third step, and operations similar to those used in the third step of Comparative Example 1-1 were carried out to synthesize the desired compound (35, 1 mg, yield in 3 stages 39%).

LCMS: m/z 745[M+H] ⁺

HPLC retention time: 1.27 min (assay conditions QC-SMD-TFA05)

Example 314

2-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-5-hydroxy-1,6,6-trimethyl-3-oxo-N-[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]pyridazine-4-carboxamide

We used ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)-2-methylpropanoate, synthesized in the second stage of Example 313, and the carboxylic acid reagent synthesized in the first stages of comparative example 81, and carried out operations similar to those used in example 313 to synthesize the desired compound (36.6 mg, yield in 3 stages 41%).

LCMS: m/z 744[M+H] ⁺

HPLC retention time: 1.28 min (assay conditions QC-SMD-TFA05)

Example 315

2-[[2,3-Difluoro-4-(3-morpholin-4-ylprop-1-ynyl)phenyl]methyl]-5-hydroxy-1,6,6-trimethyl-3-oxo-N-[4 -(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]pyridazine-4-carboxamide

First stage

2,3-Difluoro-4-iodobenzaldehyde and 3-isobutyloxy-3-oxopropionate were used and operations similar to those used in the first and second steps of Comparative Example 103 were performed to synthesize isobutyl-2-(2,3-difluoro-4-iodobenzyl) -5-hydroxy-1,6,6-trimethyl-3-oxo-1,2,3,6-tetrahydropyridazine-4-carboxylate.

LCMS: m/z 509[M+H] ⁺

HPLC retention time: 1.10 min (assay conditions SQD-FA05)

Second stage

We used isobutyl ester (2-(2,3-difluoro-4-iodobenzyl)-5-hydroxy-1,6,6-trimethyl-3-oxo-1,2,3,6-tetrahydropyridazine-4-carboxylic acid, synthesized in the first step, and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Comparative Example 50) and carried out operations similar to those used in the fifth step of Example 237 to synthesize 2-(2. 3-difluoro-4-iodobenzyl)-5-hydroxy-1,6,6-trimethyl-3-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl) -1,2,3,6-tetrahydropyridazine-4-carboxamide.

LCMS: m/z 742[M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SQD-FA05)

Third stage

The iodine-containing derivative synthesized in the second stage and 4-(prop-2-yn-1-yl)morpholine were used and operations similar to those used in Example 123 were performed to synthesize the desired compound.

LCMS: m/z 739[M+H] ⁺

HPLC retention time: 1.31 min (assay conditions QC-SMD-TFA05)

Example 316

N-[4-Chloro-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-2-[[2,3-difluoro-4-(3-morpholin-4-ylprop-1-ynyl)phenyl ]methyl]-5-hydroxy-1,6,6-trimethyl-3-oxopyridazine-4-carboxamide

The aniline reagent synthesized in Comparative Example 53 was used and operations similar to those used in Example 315 were performed to synthesize the title compound.

LCMS: m/z 705[M+H] ⁺

HPLC retention time: 1.29 min (assay conditions QC-SMD-TFA05)

Example 317

6-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-en-8-carboxamide

First stage

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylidenamino]-methylamino]cyclobutane-1-carboxylate

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride (Comparative Example 85) (300 mg, 1.67 mmol) was dissolved in acetic acid (16.7 mmol, 956 μl) and water (956 μl) and then sodium nitrite was added at 0° C. (132 mg, 1.91 mmol) and the mixture was stirred under nitrogen atmosphere for 30 minutes. Zinc (1.09 g, 16.7 mmol) was added to the reaction mixture at 0° C. and the mixture was stirred under a nitrogen atmosphere for 1.5 hours. The reaction mixture was then filtered, methanol (9.56 ml) and 2.3 -difluoro-4-(2-morpholinoethoxy)benzaldehyde (324 mg, 1.19 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate, the organic layer was washed with 1 M aqueous dipotassium hydrogen phosphate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (aminosilica gel, hexane/ethyl acetate) and the desired compound was obtained (402 mg, 82%).

LCMS: m/z 412[M+H] ⁺

HPLC retention time: 0.91 min (assay conditions SMD-TFA05)

Second stage

Methyl-1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]anilino]propanoyl]amino]-methylamino]cyclobutane-1-carboxylate

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylidenamino]-methylamino]cyclobutane-1-carboxylate (27.5 g, 66.9 mmol) was dissolved in ethyl acetate (158 ml) and then hydrochloric acid (4 M solution in ethyl acetate, 158 ml) was added at 0° C. and the mixture was stirred under nitrogen atmosphere for 10 minutes. 5-ethyl-2-methylpyridineborane (19.9 mL, 134 mmol) was added to the reaction mixture at 0° C. and the mixture was stirred under nitrogen atmosphere for 30 minutes. Then, aqueous sodium hydroxide (5 M, 115 ml) and aqueous potassium phosphate (1 M, 50.0 ml) were added to the reaction mixture, the mixture was diluted with ethyl acetate, the organic layer was washed with 1 M aqueous dipotassium hydrogen phosphate and brine, and dried over magnesium sulfate , filtered and concentrated under reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylamino]-methylamino]cyclobutane-1-carboxylate as a crude product.

Resulting crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (first step of Comparative Example 82) (27.6 g, 70.2 mmol) was dissolved in ethyl acetate (279 ml) and N,N-dimethylformamide (139 ml) was added at 0°C followed by pyridine (5.40 ml, 66.9 mmol) and 2,4,6-tripropyl-1,3 ,5,2,4,6-trioxatriphosphinan-2,4,6-trioxide (1.7 M solution in ethyl acetate, 79.0 ml, 134 mmol) and the mixture was stirred under nitrogen for 30 minutes. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous dipotassium hydrogen phosphate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.15 g, 100%).

LCMS: m/z 789.1[M+H] ⁺

HPLC retention time: 1.01 min (assay conditions SMD-FA05)

Third stage

6-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-en-8-carboxamide

Methyl-1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]anilino]propanoyl]amino]-methylamino]cyclobutane-1-carboxylate (1.14 g, 1.45 mmol) was dissolved in methanol (7.27 ml) and N,N-dimethylformamide (7, 27 ml) and then potassium carbonate (602 mg, 4.36 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 1.5 hours. Formic acid and water were added to the reaction mixture and the mixture was purified using C18 reverse column chromatography. phase (methanol/water) and obtained the desired compound (840 mg, 76%).

LCMS: m/z 757.4[M+H] ⁺

HPLC retention time: 1.27 min (assay conditions SMD-TFA05)

Although tautomers of some of the compounds of interest exist, in some cases but not in others isomers can be observed depending on the type of solvent used for the measurement. For example, ¹ H-NMR and ¹³ C-NMR of the main tautometers in chloroform-D are as follows.

Example 317: Major tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.58 (1H, s), 12.81 (1H, s), 9.60 (1H, s), 8.50 (1H, d, J=8.6 Hz), 7.95 (1H, s), 7.90 (1H, d, J=1.6 Hz), 7.80 (1H, dd, J=8.6, 1.6 Hz), 7, 02 (1H, ddd, J=8.6, _JCF =7.2, 1.6 Hz), 6.72 (1H, ddd, J=8.6, _JCF =7.2, 1.6 Hz ), 5.06 (1H, brs), 4.20 (1H, brs), 4.20 (2H, t, J=5.5 Hz), 3.74 (4H, t, J=4.1 Hz ), 2.85 (2H, brs), 2.61 (4H, brs), 2.52 (1H, m), 2.41 (3H, s), 1.85-1.83 (3H, m) , 1.73 (1H, m), 1.60 (1H, m).

¹³ C-NMR (CDCl ₃ ) δ: 186.1 (qC), 169.8 (qC), 165.7 (qC), 162.8 (qC), 159.3 (qC), 156.6 (qC , q, J=36.4 Hz), 150.4 (qC, dd, J=248.7, 10.5 Hz), 147.8 (qC, d, J=5.5 Hz), 141.3 (qC, dd, J=248.1, 14.6 Hz), 138.8 (qC), 128.3 (CH, q, J=3.3 Hz), 127.7 (qC), 127.1 (CH), 127.0 (qC, q, J=33.4 Hz), 125.1 (CH), 124.7 (CH), 123.6 (qC, q, J=271.8 Hz), 120.5 (qC, q, J=275.4 Hz), 118.2 (qC, d, J=12.4 Hz), 115.9 (CH, q, J=2.5 Hz), 109, 6 (CH, d, J=1.9 Hz), 92.3 (qC), 67.9 (CH ₂ ), 66.9 (CH ₂ ×2), 64.2 (qC), 57.5 ( CH ₂ ), 54.1 (CH ₂ ×2), 41.6 (CH ₂ ), 35.1 (CH ₃ ), 32.4 (CH ₂ ), 24.5 (CH ₂ ), 13.4 ( _CH2 ).

Example 318

7-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

First stage

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylidenamino]-methylamino]cyclopentane-1-carboxylate

Methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride (300 mg, 1.55 mmol) was dissolved in acetic acid (15.5 mmol, 887 μl) and water (887 μl) and then sodium nitrite (122 mg, 1 .77 mmol) and the mixture was stirred under a nitrogen atmosphere for 1 hour. Zinc (1.01 g, 15.5 mmol) was added to the reaction mixture at 0°C and the mixture was stirred under a nitrogen atmosphere for 1.5 hours. Then the reaction the mixture was filtered, methanol (8.87 ml) and 2,3-difluoro-4-(2-morpholinoethoxy)benzaldehyde (300 mg, 1.11 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate, the organic layer was washed with 1 M aqueous dipotassium hydrogen phosphate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (aminosilica gel, hexane/ethyl acetate) and the desired compound was obtained (375 mg, 80%).

LCMS: m/z 426.2[M+H] ⁺

HPLC retention time: 0.93 min (assay conditions SMD-TFA05)

Second stage

1-[[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin- 4-yl]anilino]propanoyl]amino]-methylamino]cyclopentane-1-carboxylic acid

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate (29.8 g, 70.3 mmol) was dissolved in ethyl acetate (172 ml) and then hydrochloric acid (4 M solution in ethyl acetate, 172 ml) was added at 0° C. and the mixture was stirred under nitrogen atmosphere for 10 minutes. 5-ethyl-2-methylpyridineborane (20.9 mL, 141 mmol) was added to the reaction mixture at 0° C. and the mixture was stirred under nitrogen atmosphere for 30 minutes. Then, aqueous sodium hydroxide (5 M, 125 ml) and aqueous potassium phosphate (1 M, 50.0 ml) were added to the reaction mixture, the mixture was diluted with ethyl acetate, the organic layer was washed with 1 M aqueous potassium phosphate and brine, and dried over sulfate magnesium, filtered and concentrated under reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylamino]-methylamino]cyclopentane-1-carboxylate as a crude product .

Resulting crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (first step of Comparative Example 82) (29.0 g, 73.8 mmol) was dissolved in ethyl acetate (293 ml) and N,N-dimethylformamide (146 ml) was added at 0°C followed by pyridine (5.67 ml, 70.3 mmol) and 2,4,6-tripropyl-1,3 ,5,2,4,6-trioxatriphosphinan-2,4,6-trioxide (1.7 M solution in ethyl acetate, 83.0 ml, 141 mmol) and the mixture was stirred under nitrogen for 30 minutes. Brine was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous dipotassium hydrogen phosphate and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was washed with methanol to give the title compound (39.4 g, 70%).

LCMS: m/z 803.1[M+H] ⁺

HPLC retention time: 1.03 min (assay conditions SMD-FA05)

Third stage

7-[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethylpyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

1-[[[2,3-Difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methyl-[3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin- 4-yl]anilino]propanoyl]amino]-methylamino]cyclopentane-1-carboxylic acid (15.0 g, 18.7 mmol) was dissolved in methanol (94.0 ml) and N,N-dimethylformamide (94.0 ml) and then potassium carbonate (7.76 g, 56.1 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 1.5 hours. Formic acid and water were added to the reaction mixture and the mixture was purified using C18 column chromatography reverse phase (methanol/water) to obtain the title compound (13.3 g, 92%).

LCMS: m/z 771.3[M+H] ⁺

HPLC retention time: 1.29 min (assay conditions SMD-TFA05)

Although tautomers of some of the compounds of interest exist, in some cases but not in others isomers can be observed depending on the type of solvent used for the measurement. For example, ¹ H-NMR and ¹³ C-NMR of the main tautometers in chloroform-D are as follows.

Example 318: Major Tautomer

¹ H-NMR (CDCl ₃ ) δ: 16.55 (1H, s), 12.83 (1H, s), 9.62 (1H, s), 8.49 (1H, d, J=8.8 Hz), 7.96 (1H, s), 7.90 (1H, d, J=1.5 Hz), 7.79 (1H, dd, J=8.8, 1.5 Hz), 7, 05 (1H, dd, J=8.1, 7.4 Hz), 6.73 (1H, dd, J=8.1, 7.4 Hz), 5.05 (1H, d, J=14, 2 Hz), 4.21 (1H, d, J=14.2 Hz), 4.19 (2H, t, J=5.7 Hz), 3.74 (4H, t, J=4.6 Hz ), 2.84 (2H, t, J=5.7 Hz), 2.60 (4H, m), 2.48 (3H, s), 2.16 (1H, m), 1.74 (2H , m), 1.59 (1H, m), 1.52 (1H, m), 1.47 (2H, m), 1.31 (2H, m).

¹³ C-NMR (CDCl ₃ ) δ: 187.7 (qC), 169.9 (qC), 165.7 (qC), 163.2 (qC), 159.3 (CH), 156.6 (qC , q, J _CF =36.3 Hz), 150.4 (qC, dd, J _CF =248.7, 10.5 Hz), 147.9 (qC, d, J _CF =5.8 Hz), 141.3 (qC, dd, J _CF =248.3, 14.7 Hz), 138.8 (qC), 128.3 (CH, q, J _CF =3.3 Hz), 127.8 (qC ), 127.1 (CH, q, J _CF =3.9 Hz), 126.9 (qC, q, J _CF =33.4 Hz), 125.5 (CH), 124.7 (CH), 123.6 (qC, q, J _CF =272.1 Hz), 120.5 (qC, q, J _CF =275.4 Hz), 117.8 (qC, d, J _CF =12.9 Hz) , 116.0 (CH, q, J _CF =2.5 Hz), 109.7 (CH), 93.1 (qC), 71.4 (qC), 68.1 (CH ₂ ), 66.9 (CH ₂ ×2), 57.5 (CH ₂ ), 54.2 (CH ₂ ×2), 41.7 (CH ₂ ), 37.6 (CH ₂ ), 36.8 (CH ₂ ), 31.4 (CH ₂ ), 24.8 (CH ₂ ), 23.3 (CH ₂ ).

Example 319

(4aR)-N-(4-Bromo-3-fluorophenyl)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro -5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

First stage

We used (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluorobenzaldehyde and then (R)-1-((2,3-difluoro-4-iodobenzylidene)amino)-2-methylpyrrolidine methyl ester -2-carboxylic acid (2.24 g, 5.49 mmol), obtained by similar steps to those used in Example 1, was dissolved in acetic acid (5.0 ml) and methanol (5.5 ml) was added followed by cyanoborohydride sodium (1.76 g, 28.0 mmol) and the mixture was stirred under nitrogen atmosphere at room temperature for 14 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-((2,3-difluoro-4-iodobenzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester in as an unrefined product.

Second stage

The crude product obtained in the first step was dissolved in tetrahydrofuran (5.5 ml) and then potassium triphosphate (2.38 g, 11.2 mmol) and chlorocarbonylacetic acid methyl ester (1.00 ml, 9. 06 mmol) and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours. Dichloromethane and 1 N were added to the reaction mixture. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S)-1-[(3-fluorobenzyl)-(2-methoxycarbonylacetyl)-amino]-pyrrolidine-2 methyl ester -carboxylic acid as a crude product.

Third stage

The resulting crude product was dissolved in N,N-dimethylformamide (1.5 ml) and then cesium carbonate (672 mg, 2.06 mmol) was added and the mixture was stirred under nitrogen atmosphere at 80°C for 5.5 hours. To the reaction mixture dichloromethane and 1 N were added. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl -2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate as a crude product.

Fourth stage

The crude product (328 mg, 0.686 mmol) obtained in the third step and 4-bromo-3-fluoroaniline (145 mg, 0.763 mmol) were dissolved in toluene (3.4 ml) and the mixture was stirred at 110°C for 1 h The reaction mixture was then allowed to cool, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (402 mg, 92%) as a grayish white solid.

LCMS: m/z 479[M+H] ⁺

HPLC retention time: 0.97 min (assay conditions SQD-FA05)

Example 320

(4aR)-1-[(2,3-Difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 273

2-Methylpropyl ether (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2 -b]pyridazine-3-carboxylic acid (comparative example 5) (100 mg, 0.192 mmol) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (comparative example 42) (73 .6 mg, 0.240 mmol) was dissolved in toluene (0.96 ml) and the mixture was stirred at 100°C for 40 minutes. The reaction mixture was then allowed to cool, concentrated under reduced pressure, and the resulting residue was purified by C18 reverse phase column chromatography to obtain the title compound (120 mg, 83%) as a white amorphous solid.

LCMS: m/z 753[M+H] ⁺

HPLC retention time: 0.93 min (SQD-FA50 assay conditions)

Example 321

(4aR)-1-[(2,3-Difluoro-4-iodophenyl)methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4-hydroxy-4a-methyl- 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 195

We used 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazine-3-carboxylic acid (Comparative Example 5) and 2',3'-dimethoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-2-amine (Comparative Example 16) and carried out the operations , similar to those used in the fourth stage of example 319, for the synthesis of the desired compound.

LCMS: m/z 744[M+H] ⁺

HPLC retention time: 1.19 min (SMD-TFA05)

Example 322

(4aR)-1-[(2,6-Difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 196

First stage

Formula 197

2,6-Difluoro-4-iodobenzaldehyde was used and operations similar to those used in the first to third stages of Example 319 were carried out for the synthesis of 2-methylpropyl ether (4aR)-1-[(2,6-difluoro-4-iodophenyl)methyl] -4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid.

LCMS: m/z 521[M+H] ⁺

HPLC retention time: 1.51 min (assay conditions SMD-TFA05)

Second stage

We used 2-methylpropyl ether (4aR)-1-[(2,6-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazin-3-carboxylic acid and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Comparative Example 42) and carried out operations similar to those used in the fourth step of Example 319 to synthesis of the desired compound.

LCMS: m/z 753[M+H] ⁺

HPLC retention time: 1.76 min (assay conditions QC-SMD-TFA05)

Example 323

(4aR)-1-[(2,3-Difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 198

We used 2-methylpropyl ether (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazin-3-carboxylic acid (comparative example 5) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (comparative example 50) and carried out operations similar to those used in the fourth steps of example 319, to synthesize the desired compound.

LCMS: m/z 754[M+H] ⁺

HPLC retention time: 0.93 min (SQD-FA50 assay conditions)

Example 324

(4aR)-1-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 276

2-Methylpropyl ether (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2 -b]pyridazine-3-carboxylic acid (Comparative Example 5) (1.086 g, 1.444 mmol), copper iodide (31.2 mg, 0.164 mmol), and 2-methyl-8-quinolinol (52.7 mg, 0.331 mmol ) was dissolved in dimethyl sulfoxide (4.1 ml) under nitrogen, tetrabutylammonium hydroxide (4.24 g, 6.54 mmol) and water (1.56 ml) were added and the mixture was stirred under nitrogen at 100°C for 5 hours. Then the reaction mixture was left to cool, 1 N was added to the reaction mixture. hydrochloric acid (5.1 ml), water (30 ml) and a suitable amount of N-acetyl-L-cysteine and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (834 mg, 90%) as a pale yellow amorphous solid.

LCMS: m/z 643[M+H] ⁺

HPLC retention time: 1.12 min (assay conditions SQD-FA05)

Example 325

(4aR)-1-[2,3-(Difluoro-4-hydroxyphenyl)methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4-hydroxy-4a-methyl- 2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

Formula 200

We used (4aR)-1-[2,3-(difluoro-4-iodophenyl)methyl]-N-[2-(2,3-dimethoxyphenyl)-4-(trifluoromethyl)phenyl]-4-hydroxy-4a-methyl -2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 321) and carried out operations similar to those used in Example 324 to synthesize the desired compound.

LCMS: m/z 634[M+H] ⁺

HPLC retention time: 1.14 min (assay conditions SQD-FA05)

Example 326

(4aR)-1-[(2,6-Difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 201

We used (4aR)-1-[(2,6-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyridin-3-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide (Example 322) and carried out operations similar to those used in Example 324 to synthesize the desired compound.

LCMS: m/z 643[M+H] ⁺

HPLC retention time: 1.12 min (assay conditions SQD-FA05)

Example 327

(4aR)-1-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 278

We used (4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 323) and carried out operations similar to those used in Example 324 to synthesize the desired compound.

LCMS: m/z 644[M+H] ⁺

HPLC retention time: 1.11 min (assay conditions SQD-FA05)

Example 328

(4aR)-1-[(2,6-Dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-(trifluoromethyl)-4-[6-(trifluoromethyl) pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 203

First stage

Formula 204

Methyl (R)-2-methylpyrrolidine-2-carboxylate hydrochloride (20 g, 111 mmol) was suspended in dichloromethane (100 ml) and then p-toluenesulfonic acid monohydrate (25 g, 145 mmol) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, toluene was added to azeotrope it and then the residue was suspended in dichloromethane (250 ml), sodium nitrite (11.4 g, 165 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours. the mixture was filtered and then concentrated under reduced pressure to obtain (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The resulting crude product (362 mg, 2.10 mmol) was dissolved in acetic acid (10 ml) and methanol (1.0 ml) was added at 9°C followed by zinc (725 mg, 11.2 mmol) and the mixture was stirred under atmosphere nitrogen at 9°C for 1 hour. The reaction mixture was then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) and 2,4-dichloro-4-hydroxybenzaldehyde (200 mg, 1.05 mmol) were added to the resulting residue, and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and then concentrated under reduced pressure and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl (R)-1-((2,6-dichloro -4-hydroxybenzylidene)amino)-2-methylpyrrolidine-2-carboxylate. The resulting product (5.3 g, 16.0 mmol) was dissolved in acetonitrile (50 ml) and then 2-(chloromethoxy)ethyltrimethylsilane (3.2 g, 19.2 mmol) and cesium carbonate (6.3 g, 19 .3 mmol) and the mixture was stirred under nitrogen atmosphere at 25°C for 24 hours. Water (100 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (100 ml) three times. The organic layer was washed with water and brine and then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the crude product methyl (R)-1-((2,6-dichloro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzylidene)amino)-2-methylpyrrolidine -2-carboxylate as a white solid. The resulting crude product was used and, by performing the first and second steps of Comparative Example 1-1, methyl-(R)-1-N-(2,6-dichloro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)- 3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylate.

LCMS: m/z 461[M+H] ⁺

HPLC retention time: 4.73 min (assay conditions Ph-SMD-TFA05)

Second stage

Formula 205

Methyl (R)-1-(N-(2,6-dichloro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylate (7.02 g, 11.6 mmol) was dissolved in dichloromethane (85 ml), trifluoroacetic acid (35 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl (R)-1-N-(2,6-dichloro-4-hydroxybenzyl)-3-isobutoxy-3 -oxopropanamide)-2-methylpyrrolidine-2-carboxylate (5.0 g, 91%). The resulting methyl (R)-1-N-(2,6-dichloro-4-hydroxybenzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylate (5.0 g, 10.5 mmol) was used ) and carried out operations similar to those used in the third step of Comparative Example 1-1, and obtained 2-methylpropyl ether (4aR)-1-[(2,6-dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl -2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid.

LCMS: m/z 443[M+H] ⁺

HPLC retention time: 1.32 min (assay conditions SMD-TFA05)

Third stage

We used 2-methylpropyl ether (4aR)-1-[(2,6-dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazin-3-carboxylic acid and 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine (Comparative Example 70) and carried out operations similar to those used in Example 21 , and the desired compound was obtained.

LCMS: m/z 677 [M+H] ⁺

HPLC retention time: 1.51 min (assay conditions SMD-TFA05)

Example 329

(4aR)-1-[2,6-(-Dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[6-(trifluoromethyl)-2-[6-(trifluoromethyl )pyridin-3-yl]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 206

We used 2-methylpropyl ether (4aR)-1-[(2,6-dichloro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1, 2-b]pyridazine-3-carboxylic acid (second step of Example 328) and 6,6'-bis(trifluoromethyl)-[2,3'-bipyridine]-3-amine (Comparative Example 44) and carried out operations similar to those used at the third stage of example 328 the desired compound was obtained.

LCMS: m/z 676 [M+H] ⁺

HPLC retention time: 1.55 min (assay conditions SMD-TFA05)

Example 330

(4aR)-1-[2,3-(Difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-(trifluoromethyl)-4-[6-(trifluoromethyl) pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide

Formula 207

First stage

Formula 282

We used methyl-(4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2- b]pyridazin-3-carboxylate (third step of Example 319) and 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine (Comparative Example 70) and operations similar to those used in the fourth step of Example 319, for the synthesis of ((4aR)-1-[(2,3-difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[2-(trifluoromethyl) -4-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-5-yl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-3-carboxamide.

LCMS: m/z 755[M+H] ⁺

HPLC retention time: 1.05 min (assay conditions SMD-TFA50)

Second stage

The iodide-containing derivative obtained in the first step was used and operations similar to those used in Example 324 were performed to synthesize the desired compound.

LCMS: m/z 645[M+H] ⁺

HPLC retention time: 1.43 min (assay conditions SMD-TFA05)

Example 331

(4aR)-N-(4-Bromo-2-iodophenyl)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo [1,2-b]pyridazine-3-carboxamide

Formula 209

First stage

Formula 283

(R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluorobenzaldehyde were used and operations similar to those used in the first to third steps of Example 319 were performed to synthesize methyl-(4aR)-1-[(2, 3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate.

Second stage

Methyl-(4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3 β-carboxylate and 4-bromo-2-iodoaniline were used as reagents and operations similar to those used in Example 21 were performed to synthesize the desired compound.

LCMS: m/z 618[M+H] ⁺

HPLC retention time: 1.16 min (assay conditions SMD-TFA05)

Comparative Example 104

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate hydrochloride

Formula 211

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylidenamino]-methylamino]cyclobutane-1-carboxylate (third step of Example 13 ) (300 mg, 0.726 mmol) was dissolved in 2-butanone (1.50 ml) and pyridine hydrochloride (84.0 mg, 0.727 mmol) was added at 25°C and the mixture was stirred under nitrogen for 30 min. Heptane (1.50 mL) and seeds (1.00 mg, 0.00222 mmol) were added to the reaction mixture, and then the mixture was stirred for 1 hour. Heptane (3.00 mL) was added to the reaction mixture, and the mixture was stirred for 16 hours and then the precipitated crystals were collected by filtration to obtain the title compound (271 mg, 88%).

Melting point: 108°C

¹ H-NMR (DMSO-D ₆ ) δ: 10.32 (1H, brs), 7.44 (1H, m), 7.29 (1H, s), 7.07 (1H, m), 4, 49 (2H, t, J=4.4 Hz), 3.72 (2H, t, J=5.0 Hz), 3.63 (3H, s), 3.55-3.36 (4H, m ), 3.44 (3H, s), 2.87 (3H, brs), 2.80 (3H, s), 2.48 (4H, m), 1.93 (2H, m).

The seed crystals used in Comparative Example 104 were prepared according to the following procedure.

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylidenamino]-methylamino]cyclobutane-1-carboxylate (75.3 mg , 0.182 mmol) was dissolved in dimethyl sulfoxide (0.317 ml) and 2 M hydrochloric acid (93.0 μl, 0.186 mmol) was added. The prepared solution (15.0 μL) was freeze-dried, 2-butanone (15.0 μL) and heptane (15.0 μL) were added to the resulting powder at 25°C, and the mixture was stirred for 4 days to obtain a precipitate.

Comparative Example 105

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate hydrochloride

Formula 212

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylidenamino]-methylamino]cyclopentane-1-carboxylate (first step of Example 14 ) (300 mg, 0.702 mmol) was dissolved in 2-butanone (3.00 ml), pyridine hydrochloride (81.0 mg, 0.701 mmol) was added at 25°C and the mixture was stirred under nitrogen for 30 min. Heptane (1.00 mL) and seeds (1.00 mg, 0.00215 mmol) were added to the reaction mixture, and then the mixture was stirred for 1 hour. Heptane (2.00 mL) was added to the reaction mixture, then the mixture was stirred in for 2 hours and the precipitated crystals were collected by filtration to obtain the title compound (225 mg, 69%).

Melting point: 97°C

¹ H-NMR (DMSO-D ₆ ) δ: 10.34 (1H, brs), 7.44 (1H, m), 7.26 (1H, s), 7.08 (1H, m), 4, 50 (2H, t, J=4.4 Hz), 3.72 (2H, t, J=5.0 Hz), 3.60 (3H, s), 3.55-3.44 (4H, m ), 3.35 (3H, s) 2.87 (3H, brs), 2.85 (3H, s), 2.25 (2H, m), 2.14 (2H, m), 1.70 ( 4H, m).

The seed crystals used in Comparative Example 105 were prepared according to the following procedure.

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylidenamino]-methylamino]cyclopentane-1-carboxylate (50.0 mg , 0.117 mmol) was dissolved in 2-butanone (0.500 ml), pyridine hydrochloride (15.0 mg, 0.130 mmol) was added at 25°C and the mixture was stirred under nitrogen for 30 min. Heptane (0.500 ml) and methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino] were added to the reaction mixture. cyclobutane-1-carboxylate hydrochloride (1.00 mg, 0.00222 mmol) and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to give a precipitate (36.6 mg).

Example 332

4-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl ]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]butanoate

Formula 213

First stage

2-Methylpropyl ester 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid acids

Formula 214

2,3-Difluoro-4-hydroxybenzaldehyde and methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride (Comparative Example 87) were used to synthesize the title compound in a similar manner to Comparative Example 1-1.

LCMS: m/z 411[M+H] ⁺

HPLC retention time: 1.18 min (SMD-TFA05)

Second stage

Formula 215

2-Methylpropyl 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid acids and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]aniline (Comparative Example 50) were used to synthesize 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10- hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene- 9-carboxamide as described in example 21.

LCMS: m/z 658[M+H] ⁺

HPLC retention time: 1.57 min (SMD-TFA05)

Third stage

Formula 216

Cesium carbonate (20.4 mg, 0.113 mmol) was added to a solution of 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (24.7 mg, 0.038 mmol) and methyl-4- bromobutyrate (24.48 mg, 0.075 mmol) in acetonitrile (0.4 ml) and the mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to 0°C, 1 N was added. aqueous hydrochloric acid solution (0.063 ml, 0.375 mmol) and the mixture was stirred for 10 minutes. The resulting mixture was diluted with N,N-dimethylformamide (0.6 ml) and purified by HPLC to give methyl 4-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9- [[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]butyrate (10.6 mg, 37%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 758[M+H] ⁺

HPLC retention time: 1.72 min (SMD-FA05)

Fourth stage

Potassium trimethylsilanolate (5.38 mg, 0.042 mmol) was added to the solution of methyl 4-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl) -2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]butyrate (10.6 mg, 0.014 mmol) in tetrahydrofuran (0.4 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, the resulting mixture was diluted with N,N-dimethylformamide (0.6 ml) and purified by HPLC to give the title compound ( 6.2 mg, 60%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 744[M+H] ⁺

HPLC retention time: 1.60 min (SMD-FA05)

Examples 333-335 used the appropriate alkyl bromides and performed operations similar to those used in Example 332 to synthesize the compounds described in the table below.

Comparative Example 106

2-Methylpropyl 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylic acid acids

Formula 217

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride was used as the starting material (Comparative Example 85) to synthesize the title compound using a procedure similar to that of Example 332.

LCMS: m/z 411 [M+H] ⁺

HPLC retention time: 1.18 min (SMD-TFA05)

Comparative Example 107

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 218

Methyl 1-(methylamino)cyclobutane-1-carboxylate hydrochloride was used as a starting material for the synthesis of the desired compound using a procedure similar to that of Example 332.

LCMS: m/z 658[M+H] ⁺

HPLC retention time: 1.48 min (SMD-TFA05) Example 336

8-[[2,3-Difluoro-4-(2-morpholine-2-oxoethoxy)phenyl]methyl]-5-hydroxy-9-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-8,9-diazaspiro[3.5]non-5-ene-6-carboxamide

Formula 219

The desired compound was synthesized from 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide and 2-chloro-1-morpholin-4-ylethanone (Kapanda, Coco N. Journal of Medicinal Chemistry, 52 (22), 7310-7314; 2009) using a procedure similar to that used in the third stage of Example 322.

LCMS: m/z 771[M+H] ⁺

HPLC retention time: 1.43 min (assay conditions SMD-TFA05)

Example 337

8-[[2,3-Difluoro-4-[2-(2-oxomorpholin-4-yl)ethoxy]phenyl]methyl]-5-hydroxy-9-methyl-7-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-8,9-diazaspiro[3.5]non-5-ene-6-carboxamide

Formula 220

The desired compound was obtained from 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide and 4-(2-hydroxyethyl)morpholin-2-one (Khromov-Borisov, N.V. and Remizov, A.L., Zhurnal Obshchei Khimii, 23, 598-605; 1953) by carrying out operations similar to those used in example 407.

LCMS: m/z 771[M+H] ⁺

HPLC retention time: 1.38 min (assay conditions SMD-TFA05)

Comparative Example 108

6-[[4-(2-Bromoethoxy)-2,3-difluorophenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-en-8-carboxamide

Formula 221

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) (3.00 g, 4.66 mmol) was dissolved in acetone (23.3 ml), then added 1,2-dibromoethane (6.85 ml, 79.0 mmol) and potassium carbonate (1.29 g, 9.32 mmol) and the mixture was stirred under nitrogen at 60°C for 15 hours. The reaction mixture was stirred at 0 °C, dichloromethane and 1 N were added. hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, the aqueous layer was separated using a phase separator, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using C18 reverse phase column chromatography (acetonitrile/water) to obtain the title compound (3.19 g, 91%) .

LCMS: m/z 749[M+H] ⁺

HPLC retention time: 1.58 min (assay conditions SMD-TFA05)

Comparative Example 109

7-[[4-(2-Bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 222

The desired compound was synthesized from 7-[(2,3-difluoro-4-hydroxybenzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidine- 4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (Example 332) using a procedure similar to that used in Comparative Example 106.

LCMS: m/z 764[M+H] ⁺

HPLC retention time: 1.62 min (assay conditions SMD-TFA05)

Example 338

6-[[2,3-Difluoro-4-[2-[methyl(oxolan-3-yl)amino]ethoxy]phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4- (trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 223

6-[[4-(2-Bromoethoxy)-2,3-difluorophenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (10.0 mg, 13.0 µmol) and N-methyltetrahydrofuran-3-amine (2.70 mg , 27.0 µmol) was dissolved in N,N-dimethylformamide (100 µl), then N-ethyl-N-isopropylpropan-2-amine (4.6 µl, 27.0 µmol) and tetrabutylammonium iodide (0.5 mg, 1.33 µmol) and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was diluted with N,N-dimethylformamide (0.5 ml) and purified by HPLC to give the title compound (8.0 mg, 78% ).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 771[M+H] ⁺

HPLC retention time: 1.31 min (assay conditions SMD-TFA05)

Examples 339-380

Suitable amines that are known from the literature or commercially available were used and operations similar to those used in Example 338 were performed to synthesize the compounds described in the table below. Note that if the amine is in the form of a hydrochloride, then the amine was not directly used in the reaction, but was used in the reaction after reacting with hydroiodic acid (57 wt.%, 2 equivalent masses) and forming the corresponding hydroiodide.

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm, 100×30 mm ID, S - 5 µm, 12 nm).

Example 381

(2S)-2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]butanedioate

Formula 224

L-Aspartate dimethyl ester hydrochloride (142 mg, 0.72 mmol) was dissolved in methanol (1.00 mL), hydroiodic acid (57 wt %, 95.0 μL) was added and the mixture was stirred for 1 min. The reaction mixture was then concentrated under reduced pressure, methanol was added, and toluene was added for azeotropic removal to obtain L-aspartate dimethyl ether hydroiodide as a crude product. The resulting amine hydroiodide and 7-[[4-(2-bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6 -(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (110 mg, 0.14 mmol) (Comparative Example 109) was dissolved in N,N- dimethylformamide (480 µl) and then potassium phosphate (92.0 mg, 0.43 mmol) and tetrabutylammonium iodide (5.3 mg, 14.0 µmol) were added and the mixture was stirred at 80°C for 2 hours. The reaction mixture was then diluted tetrahydrofuran (480 μl), potassium trimethylsilanolate (92.0 mg, 0.72 mmol) was added and the mixture was stirred at 50°C for 30 minutes and at 70°C for 2 hours. The reaction mixture was diluted with formic acid and water and the resulting the mixture was purified by HPLC to obtain the title compound (71.5 mg, 61%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (100×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 817[M+H] ⁺

HPLC retention time: 1.32 min (assay conditions SMD-TFA05)

Example 382

3-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]pentanedicarboxylate

Formula 225

First stage

Formula 226

7-[[4-(2-Bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) Pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (Comparative Example 109) and diethyl 3-aminopentanedicarboxylate were used as reagents and operations similar to those used in Example 337 were performed. , for the synthesis of diethyl-3-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]pentanedicarboxylate.

Second stage

Diethyl-3-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin- 4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]pentanedicarboxylate (48.0 mg, 54.0 µmol) was dissolved in tetrahydrofuran (200 µl), potassium trimethylsilanolate (34.7 mg, 0.27 mmol) was added and the mixture was stirred at 50°C for 30 min. The reaction mixture was diluted with formic acid and water and purified by HPLC to give the title compound (32.4 mg, 72%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 831[M+H] ⁺

HPLC retention time: 1.32 min (assay conditions SMD-TFA05)

Example 383

6-[[4-[3-[(2R)-2,3-Dihydroxypropoxy]propoxy]-2,3-difluorophenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-( trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 227

First stage

Formula 228

2-Methylpropyl 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylic acid acids (Comparative Example 106) and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]aniline (Comparative Example 13) were used as reagents and operations similar to those used in the third step of Example 149 were performed to synthesis of 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridine-3 -yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide.

Second stage

Formula 229

(S)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol (300 mg, 1.58 mmol) and triethylamine (0.33 ml, 2. 37 mmol) was dissolved in tetrahydrofuran (7.88 ml), methanesulfonyl chloride (0.15 ml, 1.89 mmol) was added at 0°C and the mixture was stirred at room temperature for 3 hours. Then 1 N was added to the reaction mixture. an aqueous dipotassium hydrogen phosphate solution and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 3-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]propylmethanesulfonate (316 mg, 75%) .

LCMS: m/z 269[M+H] ⁺

HPLC retention time: 0.77 min (assay conditions SMD-TFA05)

Third stage

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridine-3- yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (15.0 mg, 23.0 µmol) and 3-[[(4S)-2,2-dimethyl-1, 3-dioxolan-4-yl]methoxy]propylmethanesulfonate (8.77 mg, 33.0 µmol) was dissolved in acetonitrile (117 µl), cesium carbonate (22.8 mg, 233 µmol) was added and the mixture was stirred at 75°C in for 1.5 h. The reaction mixture was then cooled to room temperature, aqueous hydrochloric acid (6 N, 38.9 μl, 233 μmol) and methanol (38.9 μl) were added and the mixture was stirred at room temperature for 1 h 6 N was added to the reaction mixture. aqueous sodium hydroxide solution and then the mixture was filtered and concentrated, the resulting mixture was diluted with N,N-dimethylformamide (0.5 ml) and purified by HPLC to obtain the title compound (11.9 mg, 66%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (100×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 775[M+H] ⁺

HPLC retention time: 1.40 min (assay conditions SMD-TFA05)

Examples 384-400

Bromide (2-[2-(3-bromopropoxy)ethoxy]oxane, 2-[2-(4-bromobutoxy)ethoxy]ocane, 2-[2-(5-bromopentoxy)ethoxy]oxane, 2-[3- (3-bromopropoxy)propoxy]ocean, 2-[3-(4-bromobutoxy)propoxy]oxane, 2-[3-(5-bromopentoxy)propoxy]oxane, synthesized by a procedure similar to the first step of Example 147 using alcohol (2-(oxan-2-yloxy)ethanol, 3-(oxan-2-yloxy)propan-1-ol), and dibromides (1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane), which are known from the literature or commercially available, and 3-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]propylmethanesulfonate (Example 383), (S)-4-(( 4-bromobutoxy)methyl)-2,2-dimethyl-1,3-dioxolane (Comparative Example 74) and (S)-4-(((5-bromopentyl)oxy)methyl)-2,2-dimethyl-1, 3-dioxolane (Comparative Example 78), 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyridin-3-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, synthesized in a manner similar to the first step of Example 383 using 2-methylpropyl ether 7 -[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid (Example 332) and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]aniline (Comparative Example 13), 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5 -methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Example 383), 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) or 7-(2,3-difluoro-4-hydroxybenzyl)-10-hydroxy -6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-en-9 -carboxamide (Example 332) and carried out operations similar to those used in Example 383 to synthesize the compounds described in the table below.

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm, 100×30 mm ID, S - 5 µm, 12 nm)

Example 401

6-[[2,3-Difluoro-4-[2-(2-methoxyethoxy)ethoxy]phenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2- [6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 230

The desired compound was synthesized from 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) and 1-bromo-2-(2-methoxyethoxy)ethane using a procedure similar to that used in third stage of comparative example 383.

LCMS: m/z 746[M+H] ⁺

HPLC retention time: 1.66 min (assay conditions SMD-TFA05)

Example 402

6-(2,3-Difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl) -2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-en-8-carboxamide

First stage

Formula 231

6-(4-(2-Bromoethoxy)-2,3-difluorobenzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidine-4 -yl)phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (10.0 mg, 0.013 mmol) (Comparative Example 108) was dissolved in 1,3-dimethyl-2-imidazolidinone (100 µl) and then a 2.0 M solution of methylamine in tetrahydrofuran (400 µl, 0.800 mmol), N,N-diisopropylethylamine (4.6 µl, 0.027 mmol), then tetrabutylammonium iodide (0.5 mg, 0.001 mmol) was added and the mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, 0.5 M methanolic hydrochloric acid (80 μl, 0.040 mmol) and n-butanol were added and toluene was added for azeotropic removal to obtain 6-(2,3 -difluoro-4-(2-(methylamino)ethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl )phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide hydrochloride as a crude product.

LCMS: m/z 701[M+H] ⁺

HPLC retention time: 1.27 min (assay conditions SMD-TFA05)

Second stage

Formula 232

Crude product 6-(2,3-difluoro-4-(2-(methylamino)ethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6- (trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide hydrochloride was dissolved in 1,2-dichloroethane (0.5 ml), then oxetan-3-one was added (6.25 µl, 0.104 mmol), sodium triacetoxyborohydride (16.5 mg, 0.078 mmol) and acetic acid (10 µl, 0.175 mmol) and the mixture was stirred at room temperature for 1 hour. Additionally, oxetan-3-one ( 6.25 µl, 0.104 mmol) and sodium triacetoxyborohydride (16.5 mg, 0.078 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and diluted with N,N-dimethylformamide, the resulting mixture was purified by HPLC and the desired compound was obtained (3.8 mg, yield in 2 stages 39%).

LCMS: m/z 757[M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SMD-TFA05)

Example 403

6-(2,3-Difluoro-4-(oxetan-3-yloxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl) pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-en-8-carboxamide

Formula 233

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) was dissolved in acetonitrile (200 μl), then oxetan-3-yl 4-methylbenzenesulfonate (14.2 mg) was added , 0.062 mmol) and cesium carbonate (30.4 mg, 0.093 mmol) and the mixture was stirred at 80°C overnight. The reaction mixture was then diluted with N,N-dimethylformamide and water, and the resulting mixture was purified by HPLC to give the title compound (14.1 mg, 65%).

LCMS: m/z 700[M+H] ⁺

HPLC retention time: 1.62 min (assay conditions SMD-TFA05)

Example 404

6-[[2,3-Difluoro-4-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]phenyl]methyl]-9-hydroxy-5-methyl-7-oxo- N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 234

First stage

Formula 235

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) (100 mg, 0.16 mmol) and (S)-tert-butyl-2-(hydroxymethyl) Pyrrolidine-1-carboxylate (62.6 mg, 0.31 mmol) was dissolved in tetrahydrofuran (311 µl), then N,N,N',N'-tetramethylazodicarboxamide (53.5 mg, 0.31 mmol) and the mixture were added stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using C18 reverse phase column chromatography (acetonitrile/water) to give tert-butyl-(2S)-2-[[2.3 -difluoro-4-[[9-hydroxy-5-methyl-7-oxo-8-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-5, 6-diazaspiro[3.5]non-8-en-6-yl]methyl]phenoxy]methyl]pyrrolidine-1-carboxylate (115 mg, 90%).

LCMS: m/z 827[M+H] ⁺

HPLC retention time: 1.68 min (assay conditions SMD-TFA05)

Second stage

Formula 309

Hydrochloric acid (dioxane solution, 4 N, 1.00 ml, 4.00 mmol) was added to tert-butyl-(2S)-2-[[2,3-difluoro-4-[[9-hydroxy-5 -methyl-7-oxo-8-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-5,6-diazaspiro[3.5]non-8-ene- 6-yl]methyl]phenoxy]methyl]pyrrolidine-1-carboxylate (104 mg, 0.13 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, toluene was added for azeotropic removal to give (S)-6-(2,3-difluoro-4-(pyrrolidin-2-ylmethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6 -(trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide hydrochloride (96 mg, 100%).

LCMS: m/z 727[M+H] ⁺

HPLC retention time: 1.27 min (assay conditions SMD-TFA05)

Third stage

(S)-6-(2,3-Difluoro-4-(pyrrolidin-2-ylmethoxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6 -(trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide hydrochloride (10.0 mg, 13.0 µmol) and 1-bromo-2-methoxyethane ( 3.64 mg, 26.0 µmol) was dissolved in N,N-dimethylformamide (100 µl), then N-ethyl-N-isopropylpropan-2-amine (6.9 µl, 39.0 µmol) and tetrabutylammonium iodide (0 .5 mg, 1.31 µmol) and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was diluted with N,N-dimethylformamide (0.5 ml) and purified by HPLC to give the title compound (3.2 mg, 31%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 785[M+H] ⁺

HPLC retention time: 1.32 min (assay conditions SMD-TFA05)

Example 405

6-[[2,3-Difluoro-4-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxyphenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[ 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 237

The desired compound was synthesized from 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) and (S)-tert-butyl-3-hydroxypyrrolidine-1-carboxylate according to the procedure similar to that used in the first - third stages of example 404.

LCMS: m/z 771[M+H] ⁺

HPLC retention time: 1.30 min (assay conditions SMD-TFA05)

Example 406

6-[[2,3-Difluoro-4-[1-(2-methoxyethyl)azetidin-3-yl]oxyphenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl )-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 238

The desired compound was synthesized from 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Comparative Example 107) and tert-butyl-3-hydroxyazetidine-1-carboxylate using a procedure similar to that used in the first - the third stage of example 404.

LCMS: m/z 756 [M+H] ⁺

HPLC retention time: 1.33 min (assay conditions SMD-TFA05)

Example 407

6-[[2,3-Difluoro-4-(2-methyl-1-morpholin-4-ylpropan-2-yl)oxyphenyl]methyl]-9-hydroxy-5-methyl-7-oxo-N-[4 -(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide

Formula 239

A solution of trimethylphosphine in tetrahydrofuran (1 M) (0.109 ml, 0.109 mmol) was added over 30 s to a solution of 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo -N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (10 mg, 0.016 mmol ), 2-methyl-2-morpholinopropan-1-ol (17 mg, 0.106 mmol) and N,N,N',N'-tetramethylazodicarboxamide (18.7 mg, 0.106 mmol) in tetrahydrofuran (0.3 ml) at heating at 60°C. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was then cooled to room temperature, and the resulting mixture was purged with nitrogen to remove the solvent. The residue was dissolved in dimethylformamide and formic acid and the resulting mixture was purified by HPLC (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give the title compound (4.3 mg, 34%).

LCMS: m/z 785 [M+H] ⁺

HPLC retention time: 1.30 min (SMD-TFA05)

Examples 408-411

Suitable alkyl alcohols were used and operations similar to those used in Example 407 were performed to synthesize the compounds described in the table below.

Example 412

7-(2,3-Difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl) -2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

First stage

Formula 240

We used 7-[[4-(2-bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl )pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (20.0 mg, 0.026 mmol) (Comparative Example 109) and carried out operations similar to those used in the first stage Example 402 to obtain the crude product, 7-(2,3-difluoro-4-(2-(methylamino)ethoxy)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl) -2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide hydrochloride.

LCMS: m/z 715 [M+H] ⁺

HPLC retention time: 1.29 min (assay conditions SMD-TFA05)

Second stage

Formula 241

We used 7-(2,3-difluoro-4-(2-(methylamino)ethoxy)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-(6-( trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide hydrochloride and operations similar to those used in the second stage of Example 402 were performed to obtain the desired compound (11.3 mg, yield for 2 stages 56%).

LCMS: m/z 771 [M+H] ⁺

HPLC retention time: 1.19 min (assay conditions SMD-TFA05)

¹ H-NMR (DMSO-D ₆ ) δ: 12.72 (1H, s), 9.59 (1H, s), 8.56 (1H, s), 8.42 (1H, d, J=8 ,8 Hz), 8.24 (1H, s), 7.97 (1H, d, J=7.3 Hz), 7.16 (1H, t, J=7.3 Hz), 7.04 ( 1H, t, J=7.6 Hz), 5.07 (1H, d, J=13.7 Hz), 4.52 (2H, t, J=6.6 Hz), 4.41 (2H, t, J=6.1 Hz), 4.16 (3H, t, J=5.4 Hz), 3.66 (1H, q, J=6.5 Hz), 2.67 (2H, t, J=5.4 Hz), 2.46 (3H, s), 2.18 (3H, s), 2.01 (1H, m), 1.59 (3H, m), 1.27 (3H, m), 1.07 (1H, m).

Example 413

7-[[2,3-Difluoro-4-(oxolan-2-ylmethoxy)phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 242

The desired compound was synthesized from 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide and 2-(chloromethyl)tetrahydrofuran.

LCMS: m/z 742 [M+H] ⁺

HPLC retention time: 1.61 min (assay conditions SMD-TFA05)

Example 414

7-(4-(3-(Dimethylamino)-2,2-dimethylpropoxy)-2,3-difluorobenzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-( 6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 243

The desired compound was synthesized from 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide and 3-(dimethylamino)-2,2-dimethylpropan-1-ol according to a procedure similar to that of Example 407.

LCMS: m/z 771 [M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SQD-FA05)

¹ H-NMR (CDCl ₃ ) δ: 16.47 (1H, s), 12.87 (1H, s), 9.60 (1H, s), 8.47 (1H, d, J=8.4 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.79 (1H, d, J=8.4 Hz), 6.99 (1H, m), 6.72 ( 1H, m), 5.04 (1H, d, J=14.4 Hz), 4.4.19 (1H, d, J=14.4 Hz), 3.80 (2H, s), 2, 48 (3H, s), 2.43-2.36 (8H, m), 1.85-1.32 (10H, m), 1.02 (6H, s).

Example 415

1-(2-(2,3-Difluoro-4-((10-hydroxy-6-methyl-8-oxo-9-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidine-4- yl)phenyl)carbamoyl)-6,7-diazaspiro[4.5]dec-9-en-7-yl)methyl)phenoxy)ethyl)-1,4-diazabicyclo[2.2.2]octane-1-ium formate

Formula 244

First stage

Formula 245

Solution of 2-methylpropyl ether 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9- carboxylic acid, 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]aniline (100 mg, 0.152 mmol), 1,2-dichloroethane (151 mg, 1.52 mmol) and potassium carbonate ( 42 mg, 0.304 mmol) in N,N-dimethylformamide (1.01 ml) was heated at 60°C for 18 hours. The residue was dissolved in N,N-dimethylformamide and formic acid and the reaction mixture was purified using C18 reverse column chromatography phase on silica gel (0.1% formic acid-water/0.1% formic acid-acetonitrile) to obtain 7-(4-(2-chloroethoxy)-2,3-difluorobenzyl)-10-hydroxy-6-methyl- 8-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (91 mg , 83%).

LCMS: m/z 720 [M+H] ⁺

HPLC retention time: 1.697 min (SMD-TFA05)

Second stage

A solution of 7-(4-(2-chloroethoxy)-2,3-difluorobenzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidine- 4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (93 mg, 0.126 mmol), 1,4-diazabicyclo[2.2.2]octane (142 mg, 1.26 mmol) and potassium carbonate (175 mg, 1.26 mmol) in acetone (3.16 ml) were stirred at 60°C for 4 days. The reaction mixture was then cooled to room temperature, and the resulting mixture was purged with nitrogen to remove the solvent. The residue was dissolved in N,N-dimethylformamide and formic acid and the resulting mixture was purified by HPLC (0.1% formic acid-water/0.1% formic acid-acetonitrile) to give the title compound (78 mg, 73%).

LCMS: m/z 796[M] ⁺

HPLC retention time: 1.05 min (assay conditions SQD-FA05)

Example 416

7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-N-[2-[5-methyl-6 -(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)phenyl]-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 246

First stage

Formula 247

2-Methylpropyl ether 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-6,7 -diazaspiro[4.5]dec-9-ene-9-carboxylic acid was synthesized from methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy] phenyl]methylideneamino]methylamino]cyclopentane-1-carboxylate hydrochloride (Comparative Example 105) using a procedure similar to that used in the fourth step of Example 237.

LCMS: m/z 540 [M+H] ⁺

HPLC retention time: 1.11 min (assay conditions SMD-TFA05)

Second stage

The desired compound was synthesized from 2-methylpropyl ether 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo -6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid and 2-(5-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-4-(trifluoromethyl)aniline (Comparative Example 96) using a method similar to that used in the fifth stage of example 237.

LCMS: m/z 787 [M+H] ⁺

HPLC retention time: 1.41 min (assay conditions SMD-TFA05)

Example 417

7-(2,3-Difluoro-4-((2-((2-methoxyethyl)(methyl)amino)ethyl)amino)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4- (trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 248

First stage

Formula 249

2,3-Difluoro-4-iodobenzaldehyde and methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride were used and operations similar to those used in the third to fifth stages of Example 13 were carried out to synthesize the desired compound (2.69 g, yield from stage 3 69%) .

LCMS: m/z 768 [M+H] ⁺

HPLC retention time: 0.99 min (SQD-FA50 assay conditions)

Second stage

Formula 250

Dimethyl sulfoxide (1.07 ml) was added to a mixture of 7-(2,3-difluoro-4-iodobenzyl)-10-hydroxy-6-methyl-8-oxo-N-(4-(trifluoromethyl)-2-(6- (trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (205 mg, 0.267 mmol), copper(1) iodide (10.2 mg, 0.053 mmol ), 2-((2,6-dimethylphenyl)amino)-2-oxoacetate (20.6 mg, 0.107 mmol), potassium phosphate (284 mg, 1.336 mmol) and N1-(2-methoxyethyl)-N1-methylethane- 1,2-diamine (70.6 mg, 0.534 mmol) and the mixture was stirred under a nitrogen atmosphere at 90°C for 5 hours. An aqueous ammonia solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The residue was purified by C18 reverse phase column chromatography to give the title compound (210 mg, 95%).

LCMS: m/z 772 [M+H] ⁺

HPLC retention time: 0.83 min (assay conditions SQD-FA05)

Example 418

7-[[2,3-Difluoro-4-[4-[methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]-4-oxobutoxy]phenyl] methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec -9-ene-9-carboxamide

Formula 251

4-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl ]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]butanoate (40 mg, 0.054 mmol) (Example 332) was dissolved in N,N-dimethylformamide (1 ml), then (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (31.5 mg, 0.161 mmol), GATU (40.9 mg, 0.108 mmol) was added and N-ethyl-N-isopropan-2-amine (20.86 mg, 0.161 mmol) and the mixture was stirred at room temperature for 15 hours. Water (0.2 ml) was added to the reaction mixture and the resulting mixture was purified using a column C18 reverse phase chromatography to obtain the title compound (32 mg, 65%) as a white amorphous solid.

LCMS: m/z 921 [M+H] ⁺

HPLC retention time: 1.01 min (assay conditions SQD-FA05)

Example 419

7-[[4-[2-[2-(2,3-Dihydroxypropylamino)ethoxy]ethoxy]-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4- (trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 252

First stage

2-[2-(4-Methylphenyl)sulfonylethoxy]ethyl-4-methylbenzenesulfonate

Formula 253

2,2'-Oxydiethanol (200 mg, 1.9 mmol) and triethylamine (572 mg, 5.65 mmol) were dissolved in dichloromethane (10 ml), then tosyl chloride (898 mg, 4.7 mol) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was purified by silica gel chromatography (hexane:ethyl acetate = 2:1) to obtain the title compound (620 mg, 79%) as white plate-like crystals.

LCMS: m/z 415 [M+H] ⁺

HPLC retention time: 0.88 min (assay conditions SQD-FA05)

Second stage

2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl-4-methylbenzenesulfonate

Formula 254

7-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (100 mg, 0.152 mmol) was dissolved in acetonitrile (5 ml), then oxybis(ethane-2,1-diyl)bis was added (4-methylbenzenesulfonate) obtained in the first step (252 mg, 0.61 mmol) and cesium carbonate (49.6 mg, 0.152 mmol) and the mixture was stirred at 50°C for 4 hours. The reaction mixture was purified using a column C18 reverse phase chromatography to obtain the title compound (115 mg, 84%) as a white amorphous solid.

LCMS: m/z 900 [M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SQD-FA05)

Third stage

2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl-4-methylbenzenesulfonate obtained in the second step (30 mg, 0.033 mmol), and 3-Aminopropane-1,2-diol (9.11 mg, 0.1 mmol) was dissolved in acetonitrile (1 ml) and the mixture was stirred at 50°C for 5 hours. The reaction mixture was purified using C18 reverse phase column chromatography and the title compound (18 mg, 66%) was obtained as a white amorphous solid.

LCMS: m/z 819 [M+H] ⁺

HPLC retention time: 0.82 min (assay conditions SQD-FA05)

Example 420

7-[[2,3-Difluoro-4-[2-[2-[methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]ethoxy]ethoxy] phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5 ]dec-9-ene-9-carboxamide

Formula 255

(2R,3R,4R,5S)-6-(Methylamino)hexane-1,2,3,4,5-pentaol was used as the starting material and operations similar to those used in Example 419 were performed to synthesize the title compound.

LCMS: m/z 923 [M+H] ⁺

HPLC retention time: 0.79 min (assay conditions SQD-FA05)

Example 421

7-[[2,3-Difluoro-4-[2-[2-[2-[2-[2-[methyl-[(2R,3S,4S,5S)-2,3,4,5,6 -pentahydroxyhexyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine -4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 256

2-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol was used as the starting material and operations similar to those used in Example 419 were performed to synthesize the title compound.

LCMS: m/z 1055 [M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Example 422

7-[[2,3-Difluoro-4-[2-[2-[3-methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]-3 -oxopropoxy]ethoxy]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]- 6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 257

First stage

tert-Butyl-3-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]propanoate

Formula 258

2-[2-(2-Hydroxyethoxy)ethoxy]ethanol (2 g, 13.3 mmol) was dissolved in THF (tetrahydrofuran) (5 ml) and NaH (8 mg, 0.2 mol) was added. After stirring the mixture at room temperature for 10 minutes, tert-butylprop-2-enoate (0.5 g, 3.9 mmol) was slowly added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the resulting residue was purified using Column chromatography on silica gel (ethyl acetate) to obtain the title compound (488 mg, 45%) as a colorless, clear oil.

¹ H-NMR (CDCl ₃ ) δ: 3.68-3.65 (4H, m), 3.62-3.55 (10H, m), 2.47 (2H, t, J=6.4 Hz ), 1.44 (9H, s).

Second stage

tert-Butyl-3-[2-[2-[2-(4-methylphenyl)sulfonylethoxy]ethoxy]ethoxy]propanoate

Formula 259

tert-Butyl-3-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]propanoate (488 mg, 1.75 mmol) and triethylamine (532 mg, 5.26 mmol) were dissolved in dichloromethane (15 ml) and tosyl chloride (435 mg, 2.28 mmol) was added. After stirring the mixture at room temperature for 17 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:2) to obtain the title compound (550 mg, 73%) as a colorless, clear oil.

LCMS: m/z 450 [M+H ₂ O] ⁺

HPLC retention time: 0.90 min (assay conditions SQD-FA05)

Third stage

tert-Butyl-3-[2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethoxy]propanoate

Formula 260

Then tert-butyl 3-[2-[2-[2-(4-methylphenyl)sulfonylethoxy]ethoxy]ethoxy]propanoate (70 mg, 0.18 mmol) and 7-[(2,3-difluoro-4- hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5 ]dec-9-ene-9-carboxamide (79 mg, 0.12 mmol) was dissolved in acetonitrile (2 ml), cesium carbonate (117 mg, 1.36 mol) was added and the mixture was stirred at 70°C for 2 h Water (0.1 mL) was then added to the reaction mixture and the resulting mixture was purified by C18 reverse phase column chromatography to obtain the title compound (18 mg, 66%) as a white amorphous solid.

LCMS: m/z 874 [M+H] ⁺

HPLC retention time: 1.29 min (assay conditions SQD-FA05)

Fourth stage

3-[2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine -4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethoxy]propanoate

Formula 261

tert-Butyl-3-[2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethoxy]propanoate (100 mg, 0.114 mmol) was dissolved in dichloromethane (2 ml) and TFA (0.54 ml) was added at room temperature. After stirring the reaction mixture at room temperature for 2 hours, the filtrate was concentrated by distilling off the TPA. The resulting residue was immediately used in the next reaction.

LCMS: m/z 818 [M+H] ⁺

HPLC retention time: 1.15 min (assay conditions SQD-FA05)

Fifth stage

3-[2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine -4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethoxy]propanoate (40 mg, 0.05 mmol), 3-aminopropane -1,2-diol (9 mg, 0.1 mol) and GATU (37.2 mg, 0.1 mol) were dissolved in DMF (dimethylformamide) (1 ml), then diisopropylethylamine (12.6 mg, 0.1 mol) was added 1 mmol) and the mixture was stirred at room temperature for 15 hours. Water (0.1 ml) was added to the reaction mixture and the resulting mixture was purified using C18 reverse phase column chromatography to obtain the title compound (18 mg, 41%) as white amorphous solid.

LCMS: m/z 995 [M+H] ⁺

HPLC retention time: 1.01 min (assay conditions SQD-FA05)

Examples 423 and 424

The compounds described in the table below were synthesized by steps similar to those used in Example 422 using 2-[2-(2-hydroxyethoxy)ethoxy]ethanol as the starting material.

Examples 425 and 426

The compounds described in the table below were synthesized by steps similar to those used in Example 422 using 2-[2-hydroxyethyl(methyl)amino]ethanol as the starting material.

Example 427

7-[[2,3-Difluoro-4-[2-[2-[[(2S,3R,4S,5S)-2,3,4,5,6-pentahydroxyhexanoyl]amino]ethoxy]ethoxy]phenyl] methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec -9-ene-9-carboxamide

Formula 262

First stage

tert-Butyl-N-[2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl]carbamate

Formula 263

Then tert-butyl-N-[2-(2-hydroxyethoxy)ethyl]carbamate (28 mg, 0.137 mmol), 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl -8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (30 mg, 0.046 mmol) and TMAD (15.7 mg, 0.091 mmol) were dissolved in THF (1 ml), tributylphosphine (18.5 mg, 0.091 mmol) was added. After stirring the mixture at room temperature for 5 hours, the filtrate was concentrated and the residue was purified by C18 reverse phase column chromatography to give the title compound (28 mg, 74%) as a white amorphous solid.

LCMS: m/z 845 [M+H] ⁺

HPLC retention time: 1.25 min (assay conditions SQD-FA05)

Second stage

7-[[4-[2-(2-Aminoethoxy)ethoxy]-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 264

tert-Butyl-N-[2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6- (trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl]carbamate (30 mg, 0.036 mmol) was dissolved in ethyl acetate (0.3 ml), then a mixture of 4 N was added. HCl with ethyl acetate (1 ml) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the resulting residue was used in the next reaction without purification.

LCMS: m/z 745 [M+H] ⁺

HPLC retention time: 0.81 min (assay conditions SQD-FA05)

Third stage

7-[[4-[2-(2-Aminoethoxy)ethoxy]-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (42 mg, 0.054 mmol) and (3R,4S,5S,6R)-3 ,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-one (19.2 mg, 0.108 mmol) was dissolved in methanol (1 ml) and the resulting mixture was stirred in a sealed tube at 70°C for 20 hours. Water (0.1 ml) was added to the reaction mixture and the resulting mixture was purified by C18 reverse phase column chromatography to obtain the title compound (30 mg, 61%) as a white amorphous solid.

LCMS: m/z 923 [M+H] ⁺

HPLC retention time: 1.00 min (assay conditions SQD-FA05)

Example 428

7-[[2,3-Difluoro-4-[2-[2-[2-[2-[[(2S,3R,4S,5S)-2,3,4,5,6-pentahydroxyhexanoyl]amino] ethoxy]ethoxy]ethoxy]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl] -6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 265

The title compound was synthesized by steps similar to those used in Example 427, using tert-butyl-N-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate as the starting material.

LCMS: m/z 1011 [M+H] ⁺

HPLC retention time: 1.01 min (assay conditions SQD-FA05)

Example 429

7-[[2,3-Difluoro-4-[2-[2-[2-methoxyethyl(methyl)amino]ethoxy]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N- [4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 266

First stage

Formula 267

2-[2-(4-Methylphenyl)sulfonylethoxy]ethyl-4-methylbenzenesulfonate (79 mg, 0.192 mmol) and cesium carbonate (15.6 mg, 0.048 mmol) were added to the 7-[(2,3-difluoro-4 -hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[ 4.5]dec-9-ene-9-carboxamide (second step of Example 332) (31.5 mg, 0.048 mmol) in acetonitrile (1 ml) and the mixture was stirred at 50°C for 4 hours. After completion of the reaction, the reaction mixture was neutralized formic acid and the reaction mixture was purified by C18 reverse phase column chromatography to give 2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4- (trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl-4 -methylbenzenesulfonate (35.9 mg, 83%).

LCMS: m/z 900 [M+H] ⁺

HPLC retention time: 1.73 min (assay conditions SMD-TFA05)

Second stage

2-Methoxy-N-methylethanamine (0.043 ml, 0.399 mmol) was added to the solution of 2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4 -(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethoxy]ethyl- 4-methylbenzenesulfonate (35.9 mg, 0.04 mmol) in acetonitrile (0.6 ml) and the mixture was stirred at 50°C for 6 hours. After completion of the reaction, the reaction mixture was purified using C18 reverse phase column chromatography to obtain the desired compound (22.3 mg, 68%).

LCMS: m/z 817 [M+H] ⁺

HPLC retention time: 1.43 min (assay conditions SMD-TFA05)

Examples 430-434

Suitable alkylating agents and commercially available amines were used to synthesize the compounds described in the table below using operations similar to those used in Example 429.

Example 435

2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]ethanesulfonic acid

Formula 268

7-[[4-(2-Bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (20 mg, 26.0 µmol) (Comparative Example 109) was dissolved in N,N-dimethylformamide (200 µl ), then potassium phosphate (27.8 mg, 0.13 mmol) and tetrabutylammonium iodide (1.0 mg, 2.6 μmol) were added and the mixture was stirred at 80°C for 3 hours. The reaction mixture was then diluted with formic acid and water and filtered, the resulting mixture was purified by HPLC to give the title compound (8.0 mg, 38%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 809.1 [M+H] ⁺

HPLC retention time: 1.32 min (assay conditions SMD-TFA05)

Example 436

(2R)-2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]-3-sulfopropanoate

Formula 269

First stage

(2R)-2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]-3-methoxy-3-oxopropane-1-sulfonic acid

Formula 270

(2R)-2-[2-[2,3-Difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]-3-methoxy-3-oxopropane-1-sulfonic acid was synthesized from 7-[[4-(2-bromoethoxy)-2,3-difluorophenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (Comparative Example 109) and (R)-2-amino-3-methoxy-3-oxopropane-1 hydrochloride -sulfonic acid using a procedure similar to that used in example 381.

LCMS: m/z 867.0 [M+H] ⁺

HPLC retention time: 1.37 min (assay conditions SMD-TFA05)

Second stage

The desired compound was synthesized from (2R)-2-[2-[2,3-difluoro-4-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6 -(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]phenoxy]ethylamino]-3-methoxy-3-oxopropane-1- sulfonic acid using a procedure similar to that used in Comparative Example 381.

LCMS: m/z 853.0 [M+H] ⁺

HPLC retention time: 1.31 min (assay conditions SMD-TFA05)

Comparative Example 110

2-Chloro-N-(2-methoxyethyl)-N-methylethanamine hydrochloride

Formula 271

First stage

2-Methoxy-N-methylethanamine (17.0 g, 191 mmol) was dissolved in toluene (381 ml), then 2-bromoethanol (13.6 ml, 191 mmol) and triethylamine (26.6 ml, 191 mmol) were added and the mixture was stirred at 100°C for 2 hours. The reaction mixture was dried over magnesium sulfate and the resulting mixture was filtered and concentrated under reduced pressure to obtain 2-((2-methoxyethyl)(methyl)amino)ethanol (16.5 g) as unrefined product.

Second stage

2-((2-Methoxyethyl)(methyl)amino)ethanol (16.4 g, 124 mmol) was dissolved in ethyl acetate (124 ml), then thionyl chloride (13.4 ml, 186 mmol) was added at 0°C and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (20.5 g, 88%).

¹ H-NMR (DMSO-D ₆ ) δ: 10.36 (1H, brs), 4.00 (2H, t, J=6.8 Hz), 3.70 (2H, t, J=4.9 Hz), 3.51-3.43 (4H, m), 3.30 (3H, s), 2.81 (3H, s).

Example 437

7-[[2,3-Difluoro-5-iodo-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[ 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 272

First stage

Formula 273

7-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (500 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (2.54 ml), then N-iodosuccinimide was added (222 mg, 0.99 mmol) and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. Methanol was added to the reaction mixture and the mixture was purified by C18 reverse phase column chromatography (acetonitrile/water) to give 7-[( 2,3-difluoro-4-hydroxy-5-iodophenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidine-4- yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (569 mg, 96%).

LCMS: m/z 784.1 [M+H] ⁺

HPLC retention time: 1.67 min (assay conditions SMD-TFA05)

Second stage

7-[(2,3-Difluoro-4-hydroxy-5-iodophenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl) pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (341 mg, 0.43 mmol), 2-chloro-N-(2-methoxyethyl)-N- methylethanamine hydrochloride (82.0 mg, 0.43 mmol), cesium carbonate (425 mg, 1.31 mmol), tetrabutylammonium iodide (16.1 mg, 44.0 μmol) and methanol (17.7 μl) were dissolved in acetonitrile ( 4.35 ml) and the mixture was stirred under a nitrogen atmosphere at 65°C for 1.5 hours. An aqueous solution of formic acid was added to the reaction mixture and the resulting mixture was purified using C18 reverse phase column chromatography (acetonitrile/water) to obtain the desired compound (341 mg, 87%).

LCMS: m/z 899.2 [M+H] ⁺

HPLC retention time: 1.46 min (assay conditions SMD-TFA05)

Example 438

7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]-5-[3-methoxypropyl(methyl)carbamoyl]phenyl]methyl]-10-hydroxy-6-methyl -8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 274

First stage

Formula 275

7-[[2,3-Difluoro-5-iodo-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[ 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (140 mg, 156 µmol), Tris complex (dibenzylideneacetone)dipalladium chloroform (16.1 mg, 16.0 µmol), xantphos (9.0 mg, 16.0 µmol), lithium chloride (39.6 mg, 0.94 mmol), lithium formate (40, 5 mg, 0.78 mmol) and potassium trimethylsilanolate (60.0 mg, 0.47 mmol) were dissolved in N,N-dimethylformamide (1.04 ml), then acetic anhydride (58.5 μl, 0.62 mmol) was added ) and the mixture was stirred under a nitrogen atmosphere at 85°C for 30 minutes. N,N-Dimethylformamide and methanol were added to the reaction mixture, and the resulting mixture was purified by C18 reverse phase column chromatography (acetonitrile/water) to give 3,4-difluoro-5-[[10-hydroxy-6-methyl-8- oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl]-6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl ]-2-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzoate (98.4 mg, 77%).

LCMS: m/z 817.3 [M+H] ⁺

HPLC retention time: 1.41 min (assay conditions SMD-TFA05)

Second stage

3,4-Difluoro-5-[[10-hydroxy-6-methyl-8-oxo-9-[[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]carbamoyl] -6,7-diazaspiro[4.5]dec-9-en-7-yl]methyl]-2-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzoate (15.0 mg, 18.0 µmol) , 3-methoxy-N-methylpropan-1-amine (3.79 mg, 37.0 µmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (10.5 mg, 28.0 µmol) and N-ethyl-N-isopropylpropan-2-amine (9.6 µl, 55.0 µmol) were dissolved in N,N- dimethylformamide (100 μl) and the mixture was stirred under nitrogen atmosphere at 40°C for 2 hours. An aqueous solution of formic acid was added to the reaction mixture and the resulting mixture was purified by HPLC to obtain the title compound (8.0 mg, 38%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 902.1 [M+H] ⁺

HPLC retention time: 1.17 min (assay conditions SMD-FA05)

Comparative Example 111

5-(2-Methoxyethoxy)-2-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)aniline

Formula 276

First stage

Formula 277

2-Iodo-5-(2-methoxyethoxy)-4-(trifluoromethyl)aniline (1.30 g, 3.60 mmol) (Comparative Example 13), 4,4,4',4',5,5,5 ',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.74 g, 10.8 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1, 1'-Biphenyl]-2-yl)phosphine (172 mg, 0.36 mmol), potassium acetate (1.06 g, 10.8 mmol) and palladium acetate (40.0 mg, 0.18 mmol) were dissolved in dioxane (12.0 ml) and the mixture was stirred under a nitrogen atmosphere at 110°C for 4 hours. Ethyl acetate was added to the reaction mixture, the mixture was filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified using C18 reverse phase column chromatography (acetonitre yl/water) to obtain 5-(2-methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (183 mg, 14%).

LCMS: m/z 362.3 [M+H] ⁺

HPLC retention time: 0.99 min (assay conditions SQD-FA05)

Second stage

5-(2-Methoxyethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (183 mg, 0.51 mmol), 4-chloro-5-methyl-6-(trifluoromethyl)pyrimidine (comparative example 91) (199 mg, 1.01 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloride-dichloromethane complex (41.7 mg, 51.0 µmol) and potassium carbonate (210 mg, 1.52 mol) were dissolved in dioxane (2.94 ml) and water (0.44 ml) and the mixture was stirred under a nitrogen atmosphere at 90°C for 1 hour Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, the aqueous layer was separated using a phase separator, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (180 mg, 90%).

LCMS: m/z 396.1 [M+H] ⁺

HPLC retention time: 1.24 min (assay conditions SMD-TFA05)

Comparative Example 112

2-Methylpropyl ether 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-6,7 -diazaspiro[4.5]dec-9-ene-9-carboxylic acid

Formula 278

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate hydrochloride was used (Comparative Example 105 ) and carried out operations similar to those used in the fourth stage of example 237 to synthesize the desired compound.

LCMS: m/z 540.2 [M+H] ⁺

HPLC retention time: 1.11 min (assay conditions SMD-TFA05)

Example 439

7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-N-[5-(2-methoxyethoxy)-2-[5 -methyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)phenyl]-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

Formula 279

We used 2-methylpropyl ether 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-6, 7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid and 5-(2-methoxyethoxy)-2-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)aniline and carried out operations similar to those used in the fifth stage of example 237 to synthesize the desired compound.

LCMS: m/z 861.4 [M+H] ⁺

HPLC retention time: 1.40 min (assay conditions SMD-TFA05)

Example 440

9-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]-5-(3-pyridinyl)phenyl]methyl]-6-hydroxy-10-methyl-8-oxo -N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-9,10-diazaspiro[4.5]dec-6-ene-7-carboxamide

Formula 280

7-[[2,3-Difluoro-5-iodo-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[ 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide (10 mg, 11.0 µmol) ( example 437) was dissolved in 1,2-dimethoxyethane (80 μl), ethanol (80 μl) and water (80 μl) were added, then 3-pyridinyl borate (2.1 mg, 17.0 μmol), tetrakis(triphenylphosphine) palladium ( 3.9 mg, 3.3 µmol) and sodium carbonate (3.9 mg, 33 µmol) and the mixture was stirred at 80°C for 16 hours. The reaction mixture was then diluted with formic acid and water and filtered, the resulting mixture was purified using HPLC yielded the title compound (2.3 mg, 24%).

Purification conditions: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mm ID, S - 5 µm, 12 nm)

LCMS: m/z 850 [M+H] ⁺

HPLC retention time: 1.26 min (assay conditions SMD-TFA05)

Example 441

7-[[2,3-Difluoro-4-[2-[2-[2-[2-[2-[methyl-[(2S,3R,4R,5R)-2,3,4,5,6 -pentahydroxyhexyl]amino]-2-oxoethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-( trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-en-9-carboxamide

Formula 281

The title compound was synthesized by steps and operations similar to those used in Example 422, using 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol and tert-butyl-2-bromoacetate as original substance.

LCMS: m/z 1069 [M+H] ⁺

HPLC retention time: 1.00 min (assay conditions SQD-FA05)

Examples 442-445

The aniline of Example 417 and suitable aldehydes or ketones were used and the following steps were performed to synthesize the compounds described in the table below.

7-(2,3-Difluoro-4-((2-((2-methoxyethyl)(methyl)amino)ethyl)amino)benzyl)-10-hydroxy-6-methyl-8-oxo-N-(4- (trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide and the corresponding aldehyde or ketone were dissolved in tetrahydrofuran and at 0° 18 M sulfuric acid was added in an amount equivalent to one-fifth the amount of tetrahydrofuran. Then sodium tetrahydroborate was added in three portions and the mixture was stirred at 0°C or at room temperature for 3 hours or more. To synthesize the example compounds described in the table below, triethylamine, water and dimethyl sulfoxide were added to the reaction mixture and the resulting solution was purified by C18 reverse phase column chromatography.

Examples 446 and 447

The appropriate iodide derivative of Example 417, 3-morpholinopropan-1-amine, and 2-morpholinoethanamine, was used and operations similar to those used in Example 417 were performed to synthesize the compounds described in the table below.

Comparative Example 113

Methyl 1-((methylamino)cyclopentanecarboxylate-4-toluenesulfonate

First stage

Methyl 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylate

Formula 282

1-Aminocyclopentanecarboxylic acid hydrochloride (3.00 g, 18.1 mmol) was dissolved in methanol (18.0 ml), then thionyl chloride (1.32 ml, 18.1 mmol) was added at 0°C and the mixture was stirred under nitrogen atmosphere at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and water (6.00 ml) and triethylamine (7.55 ml, 54.3 mmol) were added to the resulting residue. To this solution were added di-tert-butyl dicarbonate (3.95 g, 18.1 mmol) and tert-butyl methyl ether (24.0 ml) and the mixture was stirred at 50°C for 1 hour. The aqueous layer was separated to the organic layer tetrahydrofuran (9.00 ml) was added and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (15.0 ml) was added to the resulting residue, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow oil.

¹ H-NMR (DMSO-D6) δ: 7.28 (1H, brs), 3.58 (3H, s), 2.10-1.80 (4H, m), 1.67-1.55 ( 4H, m), 1.36 (9H, s).

Second stage

Methyl 1-((tert-butoxycarbonyl)methylamino)cyclopentanecarboxylate

Formula 283

Methyl 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylate obtained in the first step was dissolved in 1-methyl-2-pyrrolidinone (24.0 ml), then sodium hydroxide (1.45 g, 36.2 mmol) was added and methyl iodide (3.38 ml, 54.3 mmol) and the mixture was stirred at 50°C for 7 hours. Water (30.0 ml) was added to this reaction mixture at room temperature and the resulting mixture was extracted twice with isopropyl acetate (15.0 ml). The resulting organic layer was washed successively with 10% aqueous sodium thiosulfate (15.0 ml) and 10% aqueous sodium chloride (15.0 ml). The resulting organic layer was concentrated under reduced pressure to obtain the title compound (5.88 g, 83%).

¹ H-NMR (DMSO-D ₆ ) δ: 3.60 (3H, s), 2.87 (3H, s), 2.20-2.10 (2H, m), 1.96-1.87 (2H, m), 1.75-1.60 (4H, m), 1.34 (9H, s).

Third stage

Methyl 1-(methylamino)cyclopentanecarboxylate-4-toluenesulfonate

Formula 284

The title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid using procedures similar to those used in Comparative Examples 87 and 88.

Comparative Example 114

2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde hydrochloride

Formula 285

2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde (200 mg, 0.73 mmol) was dissolved in 1 ml dimethoxyethane. Pyridine hydrochloride (85 mg, 0.73 mmol) was added and the mixture was stirred. The resulting crystals were filtered and dried under reduced pressure to obtain the title compound (68 mg, 30%).

¹ H-NMR (DMSO-D ₆ ) δ: 10.99 (1H, brs), 10.07 (1H, s), 7.73 (1H, m), 7.30 (1H, m), 4, 67 (2H, t, J=4.9 Hz), 3.75 (2H, t, J=5.1 Hz), 3.30 (3H, s), 3.30-3.74 (4H, m ), 2.87 (3H, brd, J=3.7 Hz).

Pharmacological studies

Study Example 1: Inhibitory effect on 33P04 uptake in rat small intestinal brush border membrane vesicles

Brush border membrane vesicles (BBMVs) were prepared using the upper small intestine of each female Wistar mouse (4-5 weeks old). The preparation of brush border membrane vesicles was carried out according to the method of Murer et al. (Murer H, Hopfer U, Kinne R. Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. 1976. J Am Soc Nephrol. 1998 Jan; 9 (1): 143-50). The activity of membrane vesicles of the brush border of the small intestine in relation to the transport of ³³ PO ₄ was determined using the fast filtration method. Each test compound was added at a final concentration of 1 µM to buffer A (110 mM NaCl, 60 mM mannitol and 10 mM HEPES (pH 7.5)) containing 340 kBq/ml ³³ PO ₄ , or DMSO (dimethyl sulfoxide) was added to buffer B (110 mM KCl, 60 mM mannitol and 10 mM HEPES (pH _{7.5)) containing 340 kBq/ml 33PO4} ^, and each resulting solution was added to the BBMVs sample and reacted for 60 s. Ice-cold buffer C (110 mM NaCl, 1 mM KH ₂ PO ₄ and 10 mM HEPES (pH 7.5)) was then added to each reaction mixture and the reaction mixture was immediately filtered with suction through a millipore filter. The filter was washed with buffer C and then each sample was dissolved in liquid scintillator. The amount of ^33PO ₄ absorbed by 5 BBMVs was determined using a liquid scintillation counter.

The degree of inhibition was determined using the expression below:

Inhibition rate (%) = (1 - (amount of ³³ P absorbed by BBMVs treated with administered test compound and buffer A - amount of ³³ P absorbed by BBMVs treated with administered DMSO and buffer B) / (amount of ³³ P absorbed by BBMVs , treated with injected DMSO and buffer A - the amount of ³³ P absorbed by BBMVs treated with injected DMSO and buffer B)) × 100.

The degree of inhibition of ³³ PO ₄ absorption in membrane vesicles of the brush border of the small intestine of rats when exposed to 1 μM of the test compound 5 (degree of absorption inhibition) is given in tables 40-1-40-8.

Study Example 2: Inhibitory effect on ³³ PO ₄ uptake by human cells expressing NaPi-IIb

CHO cells were transfected with human NaPi-IIb expression plasmids, and a human cell line stably expressing NaPi-IIb was generated using G418a. Human cells stably expressing NaPi-IIb were seeded in a 96-well plate and incubated overnight in an incubator containing CO ₂ . The medium was replaced with buffer A (145 mM choline chloride, 3 mM KCl, 1 mM _CaCl2 , 0.5 mM _MgCl2 , 5 mM glucose and 5 mM MES (pH 6.5)) and then replaced with buffer B (145 mM NaCl , 3 mM, 1 mM CaCl ₂ , 0.5 mM MgCl ₂ , 5 mM glucose and 5 mM MES (pH 6.5)), supplemented with each test compound at a final concentration of 1.3, 10 or 30 μM, or into buffer A supplemented with DMSO. After a given time, 1/20 of the volume of buffer A containing ³³ PO ₄ was added and reacted at room temperature. After washing with ice-cold Buffer A, liquid scintillator was added to each reaction mixture and the amount of ³³ PO ₄ absorbed was measured using a TopCount scintillation counter. The degree of inhibition was determined using the expression below:

Degree of inhibition (%) = (1 - (amount of ³³ PO ₄ absorbed in the well treated with the added test compound and buffer B - amount absorbed in the well treated with the introduced DMSO and buffer A)/(amount of ³³ PO ₄ absorbed in a well treated with injected DMSO and buffer B - the amount absorbed in the well treated with injected DMSO and buffer A))×100.

IC ₅₀ values (μM) were calculated using a straight line constructed from two points intersecting the 50% degree of inhibition. IC ₅₀ values for some compounds for uptake of ³³ PO ₄ by human cells expressing NaPi-IIb are given in Tables 41-1 through 41-7.

Study Example 3: Inhibitory effect on ³³ PO ₄ uptake by human cells expressing PiT-1

CHO cells were transfected with human PiT-1 expression plasmids or empty vectors to produce human PiT-1 expressing cells and human empty vector expressing cells. Human cells expressing PiT-1 or human cells expressing empty vector were seeded in a 96-well plate and incubated overnight in a CO ₂ -containing incubator. The medium was replaced with buffer A (145 mM choline chloride, 3 mM, 1 mM CaCl ₂ , 0.5 mM MgCl ₂ , 5 mM glucose and 5 mM MES (pH 6.5)) and then replaced with buffer B (145 mM NaCl, 3 mM KCl, 1 mM, 0.5 mM MgCl ₂ , 5 mM glucose, and 5 mM MES (pH 6.5)), supplemented with each test compound at a final concentration of 0.24, 1.2, 6, or 30 μM , or to buffer B supplemented with DMSO. After a given time, 1/20 of the volume of buffer A containing ³³ PO ₄ was added and reacted at room temperature. After washing with ice-cold Buffer A, liquid scintillator was added to each reaction mixture and the amount of ³³ PO ₄ absorbed was measured using a TopCount scintillation counter. The degree of inhibition was determined using the expression below:

Degree of inhibition (%) = (1 - (amount absorbed in a well containing human cells expressing PiT-1 to which the compound was added - amount of ³³ PO ₄ absorbed in a well containing human cells expressing an empty vector to which was added compound)/(amount of ³³ PO ₄ absorbed in a well containing human cells expressing PiT-1 to which DMSO was added - amount absorbed in a well containing human cells expressing an empty vector to which DMSO was added))×100.

IC ₅₀ values (μM) were calculated using a straight line constructed from two points intersecting the 50% degree of inhibition. Values for some compounds for uptake into human cells expressing PiT-1 are given in Table 42.

Study Example 4: Inhibitory Effect on Uptake by Human Cells Expressing PiT-2

CHO cells were transfected with human PiT-2 expression plasmids or empty vectors to produce human PiT-2 expressing cells and human empty vector expressing cells. Human cells expressing PiT-2 or human cells expressing empty vector were seeded in a 96-well plate and incubated overnight in a CO ₂ -containing incubator. The medium was replaced with buffer A (145 mM choline chloride, 3 mM, 1 mM CaCl ₂ , 0.5 mM MgCl ₂ , 5 mM glucose and 5 mM MES (pH 6.5)) and then replaced with buffer B (145 mM NaCl, 3 mM KC1, 1 mM CaCl ₂ , 0.5 mM MgCl ₂ , 5 mM glucose and 5 mM MES (pH 6.5)), supplemented with each test compound at a final concentration of 409 0.24, 1.2, 6 or 30 µM, or in buffer B supplemented with DMSO. After a given time, 1/20 of the volume of buffer A containing was added and reacted at room temperature. After washing with ice-cold Buffer A, liquid scintillator was added to each reaction mixture and the amount of ³³ PO ₄ absorbed was measured using a TopCount scintillation counter. The degree of inhibition was determined using the expression below:

Inhibition rate (%) = (1 - (amount of ³³ PO ₄ absorbed in a well containing human cells expressing PiT-2 to which the compound was added - amount of ³³ PO ₄ absorbed in a well containing human cells expressing an empty vector to which the compound was added)/(amount absorbed in a well containing human cells expressing PiT-2 to which DMSO was added - amount of ³³ PO ₄ absorbed in a well containing human cells expressing the empty vector to which DMSO was added)) ×100.

IC ₅₀ values (μM) were calculated using a straight line constructed from two points intersecting the 50% degree of inhibition. Values for some compounds for uptake of ³³ PO ₄ by human cells expressing PiT-2 are given in Table 43.

Study Example 5: Inhibition of Increase in Serum Phosphorus Concentration in Adenine-Induced Renal Failure in Rats

Adenine was forcibly administered orally to male Wistar rats (aged 7-8 weeks) to impair renal function, resulting in a model of hyperphosphatemia (Katsumata K, Kusano K, Hirata M, Tsunemi K, Nagano N, Burke SK, Fukushima N. Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int. 2003 Aug;64(2):441-50). Each test compound was mixed with food at a content of 0.1 wt. %. The animal was given a given amount of food for 3 days. The group of animals that were fed food without added test compound was used as the reference pathological group, and the group that was not exposed to adenine and fed food without added test compound was used as the normal group. 3 days after the start of administration of the test compound, blood was drawn from the jugular vein and serum was collected. Serum phosphorus concentrations were determined using the Fiske-Subarrow method. The degree of suppression of the increase in serum phosphorus concentration was determined using the expression below:

Degree of suppression (%) of increase in serum phosphorus concentration = (1 - [(serum phosphorus concentration in the pathological group given the test compound) - (serum phosphorus concentration in the normal group)]/[(serum phosphorus concentration in the reference pathological group) - (serum phosphorus concentration in the normal group)])×100.

As a result, it was confirmed that each tested compound has the effect of suppressing the increase in serum phosphorus concentration. Table 44 shows the degree of suppression (%) of the increase in serum phosphorus concentration for each test compound.

Study Example 6: Inhibition of Serum Phosphorus Increase in Adenine-Induced Renal Failure in Rats

Each rat with adenine-induced renal failure was prepared in the same way as in Study Example 5. Each test compound was mixed with food at a content of 0.05 wt. %. The animal was given a given amount of food for 8 days. The group of animals that were fed food without added test compound was used as the reference pathological group, and the group that was not exposed to adenine and fed food without added test compound was used as the normal group. 8 days after the start of administration of the test compound, blood was drawn from the jugular vein and serum was collected. Serum phosphorus concentrations were determined using the Fiske-Subarrow method. The degree of suppression of the increase in serum phosphorus concentration was determined using the expression below:

Degree of suppression (%) of increase in serum phosphorus concentration = (1 - [(serum phosphorus concentration in the pathological group given the test compound) - (serum phosphorus concentration in the normal group)]/[(serum phosphorus concentration in the reference pathological group) - (serum phosphorus concentration in the normal group)])×100.

As a result, it was confirmed that each tested compound has the effect of suppressing the increase in serum phosphorus concentration. Table 45 shows the degree of suppression (%) of the increase in serum phosphorus concentration for each test compound.

Study Example 7: Suppressive effect on increasing serum creatinine concentration in a rat model of chronic kidney disease

After removal of one kidney from each male Fischer rat (6-7 weeks of age), the rats were intravenously injected with antibodies to Thy 1.1 to establish a model of chronic kidney disease with permanently impaired renal function (Kusano K, Saito N, Segawa N, Fukushima N, Miyamoto K. Mutant FGF23 prevents the progression of chronic kidney disease but aggravates renal osteodystrophy in uremic rats. J Nutr Sci Vitaminol (Tokyo). 2009 Apr;55(2):99-105). The test compound was mixed with food at a concentration of 0.1% or 0.3 wt. %, and the mixture was given to the animals for 14 weeks. The group of animals fed the diet without the added test compound was used as the pathological reference group, and the group of animals that were not nephrected and not treated with antibodies and fed the diet without the added test compound was used as the normal group. 14 weeks after the start of administration of the test compound, blood was drawn from the abdominal aorta and serum was collected. Serum creatinine concentrations measured by enzyme assay (creatinase-sarcosine oxidase-POD method) were used as an indicator of kidney damage. The degree of suppression of the increase in serum creatinine concentration was determined using the expression below:

Degree of suppression (%) of increase in serum creatinine concentration = (1 - [(serum creatinine concentration in the pathological group given the test compound) - (serum creatinine concentration in the normal group))]/[(serum creatinine concentration in the reference group pathological group) - (serum creatinine concentration in normal group])×100

As a result, it was confirmed that each test compound has an effect of suppressing the increase in serum creatinine concentration, namely, an effect of suppressing kidney damage. Table 46 shows the degree of suppression (%) of the increase in serum creatinine concentration by the test compound.

Study Example 8: Suppressive Effect on Increased Serum Parathyroid Hormone Concentrations in a Rat Model of Chronic Kidney Disease

Using serum collected from the same animal as in Study Example 7, 14 weeks after the start of test compound administration, serum parathyroid hormone concentrations were measured by ELISA (enzyme-linked immunosorbent assay). The degree of suppression of the increase in the concentration of parathyroid hormone in the serum was determined using the expression below:

Degree of suppression (%) of increase in serum parathyroid hormone concentration = (1 - [(serum parathyroid hormone concentration in the pathological group given the test compound) - (serum parathyroid hormone concentration in the normal group)]/[(parathyroid hormone concentration in serum in the reference pathological group) - (concentration of parathyroid hormone in serum in the normal group)])×100.

As a result, it was confirmed that the test compound has an effect of suppressing the increase in serum parathyroid hormone concentration, namely, an effect of suppressing secondary hyperparathyroidism. Table 47 shows the degree of suppression (%) of the increase in the concentration of parathyroid hormone in the serum by the test compound.

Study Example 9: Suppressive Effects on Blood Vessel Calcium Deposition in a Rat Model of Chronic Kidney Disease

From the same animal as Study Example 7, the thoracic aorta was removed 14 weeks after the start of test compound administration and its dry weight was measured. The examined thoracic aorta was ashed and dissolved in a certain amount of hydrochloric acid, and then the calcium concentration in the solution was measured using the OSPC method to determine the amount of calcium per 1 g of thoracic aorta mass in a dry state (Katsumata K, Kusano K, Hirata M, Tsunemi K, Nagano N, Burke SK, Fukushima N. Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int. 2003 Aug; 64(2): 441-450). The degree of suppression of calcium deposition in the blood vessel was determined using the expression below:

Degree of suppression (%) of calcium deposition in the blood vessel = (1 - [(amount of calcium per 1 g of blood vessel dry weight in the pathological group given the test compound) - (amount of calcium per 1 g of blood vessel weight in the dry state in the normal group)]/[(the amount of calcium per 1 g of dry weight of the blood vessel in the reference pathological group) -(the amount of calcium per 1 g of dry weight of the blood vessel in the normal group)]) ×100.

As a result, it was confirmed that the test compound has an effect of suppressing calcium deposition in a blood vessel, namely, an effect of suppressing vascular calcification. Table 48 shows the degree of suppression (%) of calcium deposition in the blood vessel by the test compound.

Study Example 10: Suppressant effect on increasing serum phosphorus concentration when coadministered with sevelamer carbonate

Adenine-induced renal failure in rats was achieved in the same manner as in Study Example 5. Each of the animals was given a quantity of one of the following diets for 14 days: a diet containing the test compound at a concentration of 0.05% or 0.1 wt. . %; feed containing sevelamer carbonate at a concentration of 0.5% or 1.0 wt. %; and food containing the test compound at a concentration of 0.05 wt. %, in combination with sevelamer carbonate at a concentration of 0.5 wt. %. The group of animals fed with no added test compound and without sevelamer carbonate was used as the reference pathological group, and the group that was fed no adenine and neither test compound nor sevelamer carbonate was used as the normal group. 14 days after the start of administration of the test compound, blood was drawn from the carotid artery and serum was collected. Serum phosphorus concentrations using the Fiske-Subarrow method. The degree of suppression of the increase in serum phosphorus concentration was determined using the expression below:

Degree of suppression (%) of increase in serum phosphorus concentration = (1 - [(serum phosphorus concentration in the pathological group given the test compound) - (serum phosphorus concentration in the normal group)]/[(serum phosphorus concentration in the reference pathological group) - (serum phosphorus concentration in the normal group)])×100.

As a result, it was confirmed that the combined use of the test compound and sevelamer carbonate has an additive effect in suppressing the increase in serum phosphorus concentration. Table 49 shows the degree of suppression (%) of the increase in serum phosphorus concentration by the test compound, sevelamer carbonate, and when the test compound and sevelamer carbonate were used together.

Claims (22)

1. A pharmaceutical composition having inhibitory activity against one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic disease kidneys and chronic renal failure, or for use in the prevention or suppression of ectopic calcification, containing an effective amount of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]- 10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9- ene-9-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 2. Pharmaceutical composition according to claim 1 for use in the prevention or treatment of hyperphosphatemia. 3. Pharmaceutical composition according to claim 1 for use in the prevention or treatment of secondary hyperparathyroidism. 4. Pharmaceutical composition according to claim 1 for use in the prevention or treatment of chronic kidney disease. 5. Pharmaceutical composition according to claim 1 for use in the prevention or treatment of chronic renal failure. 6. The pharmaceutical composition according to claim 1 or 2, wherein the hyperphosphatemia is hyperphosphatemia in a patient suffering from chronic kidney disease. 7. Pharmaceutical composition according to any one of paragraphs. 1 or 4, where chronic kidney disease is stage 2 to 4 according to the GFR classification. 8. Pharmaceutical composition according to claim 1 for use in preventing or suppressing ectopic calcification. 9. Pharmaceutical composition according to claim 1 for the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and chronic renal failure, where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino] ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro [4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2. 10. Pharmaceutical composition according to claim 1 for preventing or suppressing ectopic calcification, where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy -6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9 β-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2. 11. Pharmaceutical composition according to claim 9 or 10, where the substance additionally inhibits NaPi-IIb. 12. Pharmaceutical composition according to any one of paragraphs. 9-11, where the substance inhibits NaPi-IIb, PiT-1 and PiT-2. 13. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and chronic renal failure, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2 ,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT -1 and PiT-2, wherein the phosphorus scavenger is selected from the group consisting of bixalomer, sevelamer carbonate, sevelamer hydrochloride, precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, calcium keto acid salt, lanthanum carbonate, aluminum hydroxide, sucrose oxyhydroxide of iron (III), polynuclear iron(III) oxide hydroxides, fermagate and iron(III) citrate hydrate. 14. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of a disease selected from the group consisting of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease and chronic renal failure, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2 ,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[ 6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT -1 and PiT-2, where the phosphorus scavenger is sevelamer carbonate. 15. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of hyperphosphatemia, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino ]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7- Diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is sevelamer carbonate. 16. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of secondary hyperparathyroidism, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl) amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7 α-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is sevelamer carbonate. 17. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of chronic kidney disease, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl )amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6, 7-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is sevelamer carbonate. 18. The pharmaceutical composition according to claim 1 for use in the prevention or treatment of chronic renal failure, where the composition is administered in combination with a phosphorus scavenger, and where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl )amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6, 7-diazaspiro[4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is sevelamer carbonate. 19. The pharmaceutical composition according to claim 1 for use in preventing or suppressing ectopic calcification, which is administered in combination with a phosphorus scavenger, where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino] ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro [4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is selected from the group consisting of bixalomer, sevelamer carbonate , sevelamer hydrochloride, precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, calcium salt of keto acid, lanthanum carbonate, aluminum hydroxide, iron(III) sucrose oxyhydroxide, polynuclear iron(III) oxide hydroxides, fermagate and iron(III) citrate hydrate . 20. The pharmaceutical composition according to claim 1 for use in preventing or suppressing ectopic calcification, which is administered in combination with a phosphorus scavenger, where 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino] ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro [4.5]dec-9-ene-9-carboxamide or a pharmaceutically acceptable salt thereof is a substance that inhibits one or more transporters selected from PiT-1 and PiT-2, wherein the phosphorus scavenger is sevelamer carbonate. 21. Pharmaceutical composition according to claims. 13-20, which is a combination drug containing a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1 and PiT-2, and a phosphorus scavenger. 22. Pharmaceutical composition according to claims. 13-20, where the phosphorus scavenger is administered as a separate pharmaceutical composition.