Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same

TECHNICAL FIELD

The present invention relates to a dihydropyridazine-3,5-dione derivative or a salt thereof, or a solvate of the compound or the salt. The present invention also relates to a pharmaceutical drug, a pharmaceutical composition, a sodium-dependent phosphate transporter inhibitor, and a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, containing the dihydropyridazine-3,5-dione derivative or the salt thereof, or the solvate of the compound or the salt as an active ingredient, and a method for prevention and/or treatment.

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 the salt. Further, this invention relates to a method for preventing or treating a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification and to a method for preventing or suppressing ectopic calcification.

BACKGROUND ART

Phosphorus is found in every cell and makes up 1% of a person's body weight. This element plays an essential role in sustaining life, such as the energy metabolism of cells. The concentration of phosphorus in blood is determined by absorption from the gastrointestinal tract and excretion from the kidney as well as bone formation and bone resorption and adjusted to a constant level. The phosphorus absorption in the gastrointestinal tract is performed mainly by a sodium-dependent phosphate transporter NaPi-IIb (SLC34A2) (Non-Patent Documents 1 and 2). Phosphorus in blood is filtered by renal glomerulus and reabsorbed in necessary amounts 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 regulating phosphorus in vivo. In end-stage renal failure patients and dialysis patients with impaired renal functions, phosphorus accumulates in the body, resulting in a rise in phosphorus concentration in blood, i.e., hyperphosphatemia.

Hyperphosphatemia brings about the calcification of soft tissues. Particularly, vascular calcification is considered responsible for the dysfunction of the heart, leading to the death of the patient. Hyperphosphatemia also brings about the hypersecretion of parathyroid hormones, i.e., secondary hyperparathyroidism, and causes bone lesions. Thus, hyperphosphatemia is viewed as a problematic factor that deteriorates the prognosis and QOL of end-stage renal failure patients and dialysis patients.

In the current treatment of hyperphosphatemia, phosphorus adsorbents are used for the purpose of suppressing phosphorus absorption in the gastrointestinal tract. Nonmetallic polymer adsorbents typified by sevelamer carbonate and sevelamer hydrochloride, calcium salt preparations typified by precipitated calcium carbonate, or metallic adsorbents typified by lanthanum carbonate are used as the phosphorus adsorbents. These adsorbents, however, have each been reported to have adverse reactions such as gastrointestinal disorders including constipation and diarrhea, hypercalcemia caused by a rise in serum calcium concentration, and in vivo metal accumulation. In addition, these adsorbents require a daily intake of a few grams and therefore present noncompliance problems. Accordingly, there is a strong demand for the development of novel hyperphosphatemia therapy improved in terms of these problems of the phosphorus adsorbents.

The inhibition of NaPi-IIb, which plays a major role in phosphorus absorption in the gastrointestinal tract, may suppress phosphorus absorption in the gastrointestinal tract, as with the phosphorus adsorbents, to decrease phosphorus concentration in blood (Non-Patent Documents 2 and 4). Also, PiT-1 (SLC20A1) and PiT-2 (SLC20A2), which are sodium-dependent phosphate transporters like NaPi-IIb, are partially responsible for phosphorus absorption in the gastrointestinal tract (Non-Patent Documents 1 and 6). Thus, a compound that inhibits NaPi-IIb, PiT-1, and PiT-2 can be expected to produce a stronger phosphorus absorption inhibitory effect and decrease phosphorus concentration in blood, compared with an inhibitor for only NaPi-IIb. Meanwhile, the suppression of phosphorus absorption by the inhibition of these sodium-dependent phosphate transporters is based on the mechanism of action different from that of the phosphorus adsorbents currently used. Thus, the sodium-dependent phosphate transporter inhibitor can be expected to serve as a novel preventive or therapeutic agent for hyperphosphatemia in place of the conventional phosphorus adsorbents. The sodium-dependent phosphate transporter inhibitor is further expected to exert preventive or therapeutic effects on secondary hyperparathyroidism and chronic kidney disease by decreasing phosphorus concentration in blood (Non-Patent Document 5). Chronic kidney disease (CKD) is a disease which brings about persistent kidney damage (e.g., proteinuria) or persistent deterioration in kidney function (a decrease in GFR: glomerular filtration rate). In 2012, the number of patients having the disease in Japan reached 13, 300, 000 (Non-Patent Document 7), and it has been desired to develop a new medicament for preventing or treating chronic kidney disease.

NTX1942 (Patent Document 1) and compounds described in Patent Documents 2 and 4 have been reported so far as NaPi-IIb inhibitors. Also, a compound having a pyridazine skeleton has been reported in Patent Document 3 which makes mention about the treatment of anemia, ischemia, and hypoxia by the HIF hydroxylase inhibitory activity of the compound.

CITATION LIST
Patent Documents

Patent Document 1: WO2012/006475

Patent Document 2: WO2011/136269

Patent Document 4: WO2013/062065

Non-Patent Documents

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

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

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

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

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

Non-Patent Document 6: Mol Aspects Med. 2013 April-June; 34 (2-3): 386-95.

Non-Patent Document 7: Japanese Journal of Nephrology, 2012; 54 (8); 1031-1189

SUMMARY OF INVENTION
Technical Problem

There is a strong demand for the development of novel hyperphosphatemia therapy improved in terms of these problems of the existing phosphorus adsorbents. There is also a strong demand for the development of a method for preventing or treating hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, as well as for the development of a method for preventing or suppressing ectopic calcification, which are improved in terms of these problems of the existing phosphorus adsorbents.

Solution to Problem

The present inventors have conducted diligent studies in light of the problems described above and consequently completed the present invention by finding for the first time that a compound represented by the formula (I) shown below, which largely differ in chemical structure from NaPi-IIb inhibitors known in the art, has an excellent NaPi-IIb inhibitory effect, PiT-1 inhibitory effect, and/or PiT-2 inhibitory effect, is useful in the prevention and/or treatment of hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, and has excellent drug efficacy on these diseases. Specifically, one aspect of the present invention provides compounds shown below or salts thereof, or solvates of the compounds or the salts.

One embodiment of the present invention provides the following compounds (1-1) to (1-55):

(1-1) A compound represented by the formula (I) or a salt thereof, or a solvate of the compound or the salt:

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wherein R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom or C_1-10alkyl;

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbon (C_6-10aryl)carbonyl, a group —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl; and

R⁵is a hydrogen atom or C_1-4alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above; and

(3) R¹is a hydrogen atom or linear C_1-10alkyl;

R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring, wherein the saturated heterocyclic ring is optionally substituted with one or more substituents R²;

R³is C_1-10alkyl optionally substituted with one or more substituents Rh, or R³is C_1-4alkyl substituted with Re;

R³⁷and R³⁸are each independently selected from a hydrogen atom and C_1-3alkyl;

each R²is independently selected from C_1-5alkyl and a halogen atom; and/or

two or more substituents R²on the 5- to 8-membered saturated heterocyclic ring may together form C_1-5alkylene that links the ring atoms to which they are attached;

each Rh is independently selected from a halogen atom, (C_1-4alkoxy)carbonyl, and a group —(O(CH₂)_a)_b—C_1-4alkoxy, wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4;

Re is C_6-10aryl optionally substituted with one or more substituents Ra, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;

each Rf is independently selected from a halogen atom, hydroxy, cyano, carboxy, (C_1-6alkoxy)carbonyl, C_1-6alkoxy, and C_6-10aryl optionally substituted with one or more substituents Rg;

each Rg is independently selected from a halogen atom, C_1-6alkyl, C_2-6alkynyl, and C_1-6alkoxy, wherein the alkyl, alkynyl, and alkoxy groups are each optionally substituted with one or more substituents selected from hydroxy and cyano;

each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴²(wherein q1 is an integer selected from 1 to 4, and q2 is an integer selected from 2 to 6), a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴(wherein r1 is an integer selected from 1 to 4, and r2 is an integer selected from 1 to 4), a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶(wherein s1 and s2 are each independently an integer selected from 2 to 4), a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²(wherein y1 is an integer selected from 1 to 4, and y2 is an integer selected from 1 to 4);

R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)C_1-6alkoxy, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR³⁹R⁴⁰, wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and —C(O)NR⁵³R⁵⁴;

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb, Rc, and Rd are each independently selected from optionally C_1-4alkoxy-substituted C_1-5alkoxy, a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, a group —SF₅, cyano, hydroxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴;

each R¹⁴is independently selected from a halogen atom, oxo, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, a group —NR²⁷R²⁸, a group —SO₂NR³⁵R³⁶, C_1-4alkylthio, and 5- to 10-membered heterocycloalkyl;

R²⁷and R²⁸are each independently selected from a hydrogen atom and C_1-4alkyl optionally substituted with (C_1-4alkoxy)carbonyl;

R³⁵and R³⁶are each independently selected from a hydrogen atom and C_1-4alkyl;

R³⁹is a hydrogen atom, or optionally C_1-6alkoxy-substituted C_1-6alkyl;

R⁴⁰is a hydrogen atom, optionally C_1-6alkoxy-substituted C_1-6alkyl, ((C_1-4alkoxy)carbonyl)C_1-6alkyl, hydroxy-substituted C_1-6alkyl, a group —(CH₂)_u—NR⁵⁵R⁵⁶(wherein u is an integer selected from 1 to 4), a group —CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷(wherein v1 is an integer selected from 0 to 2, and v2 is an integer selected from 1 to 3), a group —(CH₂)_w—SO₃H (wherein w is an integer selected from 1 to 4), a group —(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H (wherein x1 is an integer selected from 0 to 2, and x2 is an integer selected from 1 to 3), 3- to 6-membered oxacycloalkyl, or a group —(CH₂)_t1—O—(CH₂)_t2—C(O)NR⁵⁸R⁵⁹(wherein t1 and t2 are each independently an integer selected from 1 to 3);

R⁴¹is a hydrogen atom or C_1-3alkyl;

R⁴²is C_1-8alkyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)C_1-4alkyl;

R⁴³is a hydrogen atom or C_1-3alkyl;

R⁴⁴is C_1-8alkyl substituted with one or more hydroxy groups, or

R⁴³and R⁴⁴together with the nitrogen atom to which they are attached may form morpholino;

R⁴⁵is a hydrogen atom or C_1-3alkyl;

R⁴⁶is C_1-6alkyl substituted with one or more hydroxy groups;

R⁴⁷is C_1-3alkyl;

R⁴⁸is (C_1-3alkoxy)C_1-4alkyl;

R⁴⁹is a hydrogen atom and C_1-4alkyl;

R⁵⁰is —(CH₂)_z—NR⁶⁰R⁶¹(z is an integer selected from 1 to 4, R⁶⁰is a hydrogen atom or C_1-4alkyl, and R⁶¹is (C_1-3alkoxy)C_1-4alkyl, or R⁶⁰and R⁶¹together with the nitrogen atom to which they are attached may form morpholino);

R⁵¹is a hydrogen atom or C_1-4alkyl;

R⁵²is C_1-8alkyl substituted with one or more hydroxy groups;

R⁵³and R⁵⁴are each independently selected from a hydrogen atom and C_1-4alkyl;

R⁵⁵is a hydrogen atom or C_1-4alkyl;

R⁵⁶is (C_1-4alkyl)carbonyl;

R⁵⁷is a hydrogen atom or C_1-4alkyl;

R⁵⁸is a hydrogen atom or C_1-3alkyl; and

R⁵⁹is C_1-8alkyl substituted with one or more hydroxy groups.

(1-2) The compound according to (1-1) or a salt thereof, or a solvate of the compound or the salt, wherein

each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR³⁹R⁴⁰, wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups); and

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-6alkoxy-substituted C_1-6alkyl.

(1-3) The compound according to (1-1) or (1-2) or a salt thereof, or a solvate of the compound or the salt, wherein

3- to 10-membered heterocycloalkyloxy in the definition of Ra is 3- to 6-membered heterocycloalkyloxy;

3- to 10-membered heterocycloalkyl in the definition of R¹⁰, R¹¹, R¹², R¹³and R¹⁵is 3- to 6-membered heterocycloalkyl; and

5- to 10-membered heteroaryl in the definition of R¹⁰, R¹¹, R¹², R¹³and R¹⁵is 5- to 6-membered heteroaryl.

(1-4) The compound according to any of (1-1) to (1-3) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom;

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and

Rd is cyano, hydroxy, a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(1-5) The compound according to any of (1-1) to (1-4) or a salt thereof, or a solvate of the compound or the salt, wherein

each Ra is independently selected from a halogen atom, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—NR⁵¹R⁵²;

R¹⁰is carboxy, 3- to 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, or a group —(O(CH₂)_o)_p—OH;

R¹¹is hydroxy, carboxy, 5- or 6-membered heterocycloalkyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH, C_3-6cycloalkyl optionally substituted with one or more hydroxy groups or a group —NR³⁹R⁴⁰;

R¹²is a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)C_1-6alkoxy, (C_1-3alkoxy)carbonyl, 3- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or a group —NR³⁹R⁴⁰, wherein the 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholinyl, (C_1-3alkyl)sulfonyl, and —C(O)NR⁵³R⁵⁴;

R¹³is 5- or 6-membered heterocycloalkyl; and

o and p are each independently an integer selected from 2 to 4.

(1-6) The compound according to any of (1-1) to (1-5) or a salt thereof, or a solvate of the compound or the salt, wherein

each Ra is independently selected from a halogen atom, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from carboxy, 3- to 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

each R¹¹is independently selected from hydroxy, carboxy, 5- or 6-membered heterocycloalkyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH, and C_3-6cycloalkyl optionally substituted with one or more hydroxy groups;

each R¹²is independently selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 3- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, and a group —NR³⁹R⁴⁰;

R¹³is 5- or 6-membered heterocycloalkyl; and

o and p are each independently an integer selected from 2 to 4.

(1-7) The compound according to any of (1-1) to (1-5) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, [HO—((CH₂)_oO)_p]C_1-6alkyl, (C_1-6alkoxy)C_1-8alkyl optionally substituted with one or more hydroxy groups, C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (C_1-6alkoxy)C_1-8alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (pyridinyl)C_1-4alkoxy, (pyrimidinyl)C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((C_1-3alkoxy)C_1-4alkyl)amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (carboxy)C_2-6alkynyl, (3- to 6-membered heterocycloalkyl)C_2-6alkynyl optionally substituted with one or more oxo groups, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl optionally substituted with one or more hydroxy groups, (C_3-6cycloalkyl)C_2-6alkynyl optionally substituted with one or more hydroxy groups, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_2-6alkynyl, (C_1-3alkoxy)carbonyl, (morpholino)C_1-4alkylthio optionally substituted with one or more oxo groups, 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(1-8) The compound according to any of (1-1) to (1-7) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, hydroxy, cyano, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy (the morpholino moiety is optionally substituted with one or two substituent(s) selected from oxo and C_1-3alkyl), (C_1-6alkoxy)C_1-8alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (pyrrolidinyl)C_1-4alkoxy (the pyrrolidinyl moiety is optionally substituted with (C_1-3alkyl)C_1-4alkoxy), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(oxetanyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)carbonyl.

(1-9) The compound according to any of (1-1) to (1-8) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, hydroxy, cyano, C_1-3alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy substituted with one or more hydroxy groups, (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, and (C_1-3alkoxy)carbonyl.

(1-10) The compound according to any of (1-1) to (1-9) or a salt thereof, or a solvate of the compound or the salt, wherein R³is methyl substituted with Re.

(1-11) The compound according to any of (1-1) to (1-10) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one or more substituents Ra on the benzene ring.

(1-12) The compound according to any of (1-1) to (1-11) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one to three substituents Ra on the benzene ring.

(1-13) The compound according to any of (1-1) to (1-6), and (1-10) to (1-12) or a salt thereof, or a solvate of the compound or the salt, wherein Re is phenyl optionally substituted with one to three substituents Ra;

the one to three substituents Ra 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 is a halogen atom or C_1-3alkoxy;

Rj is a halogen atom, nitro, or cyano; and

Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, or a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵².

(1-14) The compound according to (1-13) or a salt thereof, or a solvate of the compound or the salt, wherein

Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, or a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²;

each R¹⁰is independently carboxy, hydroxy, morpholinyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, or a group —(O(CH₂)_o)_p—OH;

each R¹¹is independently hydroxy, carboxy, morpholinyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH, C_3-6cycloalkyl optionally substituted with one or more hydroxy groups or a group —NR³⁹R⁴⁰;

wherein the 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholinyl, (C_1-3alkyl)sulfonyl, and —C(O)NR⁵³R⁵⁴;

R¹³is morpholinyl; and

o and p are each independently an integer selected from 2 to 4.

(1-15) The compound according to any of (1-1) to (1-6) and (1-10) to (1-13) or a salt thereof, or a solvate of the compound or the salt,

wherein Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom or C_1-3alkoxy;

Rj is a halogen atom, nitro, or cyano; and

Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², or C_1-4alkylthio optionally substituted with one or more substituents R¹³.

(1-16) The compound according to (1-14) or (1-15) or a salt thereof, or a solvate of the compound or the salt,

wherein Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², or C_1-4alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from hydroxy, carboxy, morpholinyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

each R¹is independently selected from hydroxy, carboxy, morpholinyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH, and C_3-6cycloalkyl optionally substituted with one or more hydroxy groups;

each R¹²is independently selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 3- to 6-membered heterocycloalkyl, pyridinyl, pyrroryl, and a group —NR³⁹R⁴⁰;

R¹³is morpholinyl; and

o and p are each independently an integer selected from 2 to 4.

(1-17) The compound according to (1-13) or (1-14) or a salt thereof, or a solvate of the compound or the salt, wherein Rk is a halogen atom, hydroxy, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, [HO—((CH₂)_oO)_p]C_1-6alkyl, (C_1-6alkoxy)C_1-8alkyl optionally substituted with one or more hydroxy groups, C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (C_1-6alkoxy)C_1-8alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety contains one to three heteroatoms selected from O or N, and is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl moiety is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (pyridinyl)C_1-4alkoxy, (pyrimidinyl)C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkoxy(C_1-3alkyl))amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (carboxy)C_2-8alkynyl, (3- to 6-membered heterocycloalkyl)C_2-6alkynyl optionally substituted with one or more oxo groups, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl optionally substituted with one or more hydroxy groups, (C_3-6cycloalkyl)C_2-6alkynyl optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, (morpholino)C_1-4alkylthio, 3- to 6-membered oxacycloalkyloxy, or 3- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(1-18) The compound according to any of (1-13), (1-14) and (1-17) or a salt thereof, or a solvate of the compound or the salt, wherein Rk is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (pyrrolidinyl)C_1-4alkoxy (the pyrrolidinyl moiety is substituted with (C_1-3alkyl)C_1-4alkoxy), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(oxetanyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, (carboxy)C_2-8alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)carbonyl.

(1-19) The compound according to any of (1-13) to (1-18) or a salt thereof, or a solvate of the compound or the salt, wherein Rk is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy substituted with one or more hydroxy groups, (carboxy)C_2-8alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)carbonyl.

(1-20) The compound according to any of (1-1) to (1-19) or a salt thereof, or a solvate of the compound or the salt,

wherein R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom or C_1-6alkyl;

R⁴is C_1-4alkyl optionally substituted with one or more halogen atom(s), or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above; and

(3) R¹is a hydrogen atom or linear C_1-6alkyl;

R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring.

(1-21) The compound according to any of (1-1) to (1-3), (1-10) to (1-12), and (1-20) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is C_1-6alkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom, C_2-6alkynyl optionally substituted with one or more substituents R¹, C_1-6alkoxy optionally substituted with one or more substituents R¹², 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²;

R¹¹and R¹²are each independently selected from halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy, (C_1-4alkoxy)C_1-6alkoxy, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and a group —NR³⁹R⁴⁰, wherein the 3- to 6-membered heterocycloalkyl group is optionally substituted with one or two substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and —C(O)NR⁵³R⁵⁴;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb, Rc, and Rd are each independently selected from a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, phenyl optionally substituted with one or more substituents R¹⁴, and 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy, a group —SO₂NR³⁵R³⁶(wherein R³⁵and R³⁶are each independently selected from C_1-4alkyl), and C_1-4alkylthio.

(1-22) The compound according to any of (1-1) to (1-3), (1-5) to (1-7), (1-10) to (1-12), (1-20), and (1-21) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (C_1-4alkoxy)C_1-6alkoxy (the C_1-4alkoxy moiety is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-6alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety is optionally substituted with one or two substituents selected from oxo, a halogen atom, C_1-4alkyl optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((C_1-3alkoxy)C_1-4alkyl)amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy optionally substituted with one or more halogen atoms, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (3- to 6-membered heterocycloalkyl)C_2-6alkynyl (the heterocycloalkyl moiety is optionally substituted with one or more oxo groups), [N—((C_1-3alkoxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(1-23) The compound according to any of (1-1) to (1-3), (1-10) to (1-13), (1-20), and (1-21) or a salt thereof, or a solvate of the compound or the salt, wherein Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom;

Rj is a halogen atom; and

Rk is a halogen atom, 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyl moiety comprises one heteroatom selected from O and N and is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), optionally R¹¹-substituted C_2-6alkynyl, optionally R¹²-substituted C_1-6alkoxy, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, a group —NR⁴⁹R⁵⁰, or a group —(O(CH₂)_y1)_y2—O—CH₂—CH(O)NR⁵¹R⁵².

(1-24) The compound according to (1-21) or (1-23) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹¹is morpholino;

R¹²is selected from 5- to 6-membered heterocycloalkyl which contains one or two hetero atoms selected from O and N, (C_1-4alkoxy)C_1-6alkoxy or a group —NR³⁹R⁴⁰.

(1-25) The compound according to any of (1-13), (1-14), (1-17) and (1-23) or a salt thereof, or a solvate of the compound or the salt,

wherein Rk is [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (C_1-4alkoxy)C_1-6alkoxy (the C_1-4alkoxy moiety is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-6alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety comprises one to three hetero atom(s) which is selected from O or N and is optionally substituted with one or two substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl moiety is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkoxy(C_1-4alkyl))amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (3- to 6-membered heterocycloalkyl)C_2-6alkynyl optionally substituted with one or more oxo groups (the heterocycloalkyl moiety comprises one to three hetero atoms selected from O and N), [N—((C_1-3alkoxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_2-6alkynyl, 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(1-26) The compound according to any of (1-1) to (1-3), (1-5), (1-7), (1-8), (1-10) to (1-20), and (1-21) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is C_1-6alkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom, optionally R¹¹-substituted C_2-6alkynyl, and optionally R¹²-substituted C_1-6alkoxy;

R¹¹and R¹²are each independently selected from 5- or 6-membered heterocycloalkyl and —NR³⁹R⁴⁰;

R³⁹and R⁴⁰are each independently selected from hydrogen atom and optionally C_1-6alkoxy-substituted C_1-6alkyl;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

(1-27) The compound according to any of (1-1) to (1-26) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, phenyl optionally substituted with one or more substituents R¹⁴, or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(1-28) The compound according to any of (1-1) to (1-12), (1-20), (1-21), (1-23), (1-26) and (1-27) or a salt thereof, or a solvate of the compound or the salt, wherein

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

R¹¹and R¹²are each independently selected from morpholinyl and a group —NR³⁹R⁴⁰;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl;

Ar¹is phenyl, pyridinyl, or pyrimidinyl, wherein the phenyl, pyridinyl, and pyrimidinyl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, phenyl, pyridinyl, or pyrimidinyl, wherein the phenyl, pyridinyl, and pyrimidinyl groups are each optionally substituted with one or more substituents R¹⁴.

(1-29) The compound according to any of (1-1) to (1-4), (1-10) to (1-17), (1-20), (1-21), (1-23), and (1-26) to (1-28) or a salt thereof, or a solvate of the compound or the salt, wherein

Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom;

Rj is a halogen atom; and

Rk is hydroxy, C_2-6alkynyl optionally substituted with a substituent R¹¹, or C_1-6alkoxy optionally substituted with a substituent R¹².

(1-30) The compound according to any of (1-26) to (1-29) or a salt thereof, or a solvate of the compound or the salt, wherein R¹¹and R¹²are each independently selected from morpholinyl, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino] and [N,N-di(C_1-3alkyl)amino].

(1-31) The compound according to any of (1-26) to (1-30) or a salt thereof, or a solvate of the compound or the salt, wherein R¹¹and R¹²are each independently selected from morpholinyl, and [N-((methoxy)ethyl)-N-(methyl)amino].

(1-32) The compound according to any of (1-1) to (1-31) or a salt thereof, or a solvate of the compound or the salt, wherein R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring, and R⁴is C_1-4alkyl.

(1-33) The compound according to any of (1-1) to (1-3), (1-5), (1-6), (1-10) to (1-12) and (1-20) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring;

R⁴is C_1-4alkyl;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom and C_1-4alkoxy optionally substituted with one or more substituents R¹²;

each R¹²is independently selected from 5- or 6-membered heterocycloalkyl and —NR³⁹R⁴⁰;

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-4alkoxy-substituted C_1-4alkyl;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb, Rc, and Rd are each independently selected from a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, and 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, and C_1-4alkylthio.

(1-34) The compound according to any of (1-1) to (1-33) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is a halogen atom or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(1-35) The compound according to any of (1-1) to (1-34) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one to three substituents Ra on the benzene ring.

(1-36) The compound according to any of (1-1) to (1-35) or a salt thereof, or a solvate of the compound or the salt, wherein Ra is selected from a halogen atom, (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, or [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(1-37) The compound according to any of (1-1) to (1-5), (1-10) to (1-16), (1-20), and (1-33) to (1-36) or a salt thereof, or a solvate of the compound or the salt, wherein

Re is phenyl optionally substituted with one to three substituents Ra;

Ri and Rj are each independently a halogen atom; and

Rk is C_1-4alkoxy optionally substituted with one or more substituents R¹².

(1-38) The compound according to any of (1-13) to (1-18), (1-20), (1-25), (1-29) and (1-37) or a salt thereof, or a solvate of the compound or the salt, wherein

Rk is a halogen atom, (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(1-39) The compound according to any of (1-1) to (1-6), (1-10) to (1-16), (1-20) to (1-23), (1-26), (1-33) to (1-35), (1-37) and (1-38) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is phenyl or pyridinyl;

Rd is pyridinyl or pyrimidinyl;

R¹²is selected from morpholinyl, [N-(2-(methoxy)ethyl)-N-(methyl)amiono], [N,N-dimethylamino].

(1-40) The compound according to any of (1-1) to (1-39) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom, methyl or trifluoromethyl;

Rd is a halogen atom, trifluoromethyl, phenyl optionally substituted with one to three substitutrents R¹⁴and 5- to 6-membered heteroaryl optionally substituted with one to three substitutrents R¹⁴, wherein the heteroaryl comprises one to three hetero atoms selected from O, S, and N.

(1-41) The compound according to any of (1-1) to (1-40) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹⁴is each independently selected from methyl, trifluoromethyl, cyano, nitro, a halogen atom, methoxy, ethoxy, trifluoromethoxy, methylthio, methoxycarbonyl and dimethylaminosulfonyl.

(1-42) The compound according to any of (1-1) to (1-41) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹⁴is each independently selected from methyl, trifluoromethyl, cyano, a chlorine atom and methylthio.

(1-43) The compound according to any of (1-1) to (1-42) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is phenyl or 5- to 6-membered heteroaryl which comprises one to three hetero atoms selected from O, S, and N, wherein the phenyl and the heteroaryl is substituted with one to three substituents selected from Rb, Rc, and Rd.

(1-44) The compound, according to any of (1-1) to (1-11), (1-20) to (1-22), (1-24), (1-26) to (1-28), (1-30) to (1-36), and (1-39) to (1-43) or a salt thereof, or a solvate of the compound or the salt, wherein the compound is represented by the formula (I-c);

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wherein, n1 is an interger selected from 1 to 4, n2 is an interger selected from 0 or more, R¹, R⁴, R⁵, Ar¹, Ra, Rb, Rc, Rd, Re are as defined in any of (1-1) to (1-11), (1-20) to (1-22), (1-24), (1-26) to (1-28), (1-30) to (1-36), and (1-39) to (1-43).

(1-45) The compound according to (1-44) or a salt thereof, or a solvate of the compound or the salt, wherein n1 is 1 and n2 is 3.

(1-46) The compound, according to any of (1-13) to (1-20), (1-23) to (1-25), (1-29) to (1-32) and (1-37) to (1-43) or a salt thereof, or a solvate of the compound or the salt, wherein the compound is represented by the formula (I-d);

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wherein n1 is an interger selected from 1 to 4, n3, n4 and n5 is a interger independently selected from 0 or 1, provided that at least one of n3, n4 and n5 is 1, R¹, R⁴, R⁵, Ar¹, Ra, Rb, Rc, Rd, Re, Ri, Rj, and Rk are as defined in any of (1-13) to (1-20), (1-23) to (1-25), (1-29) to (1-32), and (1-37) to (1-43).

(1-47) The compound according to (1-46) or a salt thereof, or a solvate of the compound or the salt, wherein n1 is 1.

(1-48) The compound according to any of (1-1) to (1-47) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is 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) A compound selected from:

(4aR)-1-[(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)—N-[2-(6-cyano-5-methylpyrimidin-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;
(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-ynoic 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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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-morpholin-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-morpholin-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-morpholin-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-pyridazine-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-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-[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-[6-(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]butanedioic acid;
3-[2-[2,3-difluoro-4-[[1-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]pentanedioic 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-ene-8-carboxamide;
7-[[2,3-difluoro-4-[2-[methyl(oxetan-3-yl)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;
7-(2,3-difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-1-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,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;
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;
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]ethanesulfonic acid; and
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]ethanesulfonic acid

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

(1-50) The compound according to any of (1-1) to (1-49) or the salt thereof, or the solvate of the compound or the salt for use in the prevention and/or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure.

(1-51) A NaPi-IIb inhibitor comprising a compound according to any of (1-1) to (1-49) or a salt thereof, or a solvate of the compound or the salt.

(1-52) A PiT-1 inhibitor comprising a compound according to any of (1-1) to (1-49) or a salt thereof, or a solvate of the compound or the salt.

(1-53) A PiT-2 inhibitor comprising a compound according to any of (1-1) to (1-49) or a salt thereof, or a solvate of the compound or the salt.

(1-54) A preventive and/or therapeutic agent for a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, the agent comprising a compound according to any of (1-1) to (1-49) or a salt thereof, or a solvate of the compound or the salt as an active ingredient.

(1-55) A method for preventing and/or treating a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, comprising administering a therapeutically effective amount of a compound according to any of (1-1) to (1-49) or a salt thereof, or a solvate of the compound or the salt to a patient.

Another embodiment of the present invention provides the following compounds (2-1) to (2-26):

(2-1) A compound represented by the formula (I) or a salt thereof, or a solvate of the compound or the salt:

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wherein R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom or C_1-10alkyl;

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbonyl, (C_6-10aryl)carbonyl, a group —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl; and

R⁵is a hydrogen atom or C_1-4alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above; and

(3) R¹is a hydrogen atom or linear C_1-10alkyl;

R³is C_1-10alkyl optionally substituted with one or more substituents Rh or C_1-4alkyl substituted with Re;

R³⁷and R³⁸are each independently selected from a hydrogen atom and C_1-3alkyl;

each R²is independently selected from C_1-5alkyl and a halogen atom; and/or

two or more substituents R²on the 5- to 8-membered saturated heterocyclic ring may together form C_1-5alkylene that links the ring atoms to which they are attached;

each Rh is independently selected from a halogen atom, (C_1-4alkoxy)carbonyl, and a group —(O(CH₂)_a)_b—C_1-4alkoxy (wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4);

Re is C_6-10aryl optionally substituted with one or more substituents Ra or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;

each Rf is independently selected from a halogen atom, hydroxy, cyano, carboxy, (C_1-6alkoxy)carbonyl, C_1-6alkoxy, and C_6-10aryl optionally substituted with one or more substituents Rg;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR³⁹R⁴⁰, wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups);

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

R²⁷and R²⁸are each independently selected from a hydrogen atom and optionally (C_1-4alkoxy)carbonyl-substituted C_1-4alkyl;

R³⁵and R³⁶are each independently selected from a hydrogen atom and C_1-4alkyl; and

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-6alkoxy-substituted C_1-6alkyl.

(2-2) The compound according to (2-1) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom;

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and

(2-3) The compound according to (2-1) or (2-2) or a salt thereof, or a solvate of the compound or the salt, wherein

each R¹⁰is independently selected from carboxy, 3- to 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

R¹³is 5- or 6-membered heterocycloalkyl; and

o and p are each independently an integer selected from 2 to 4.

(2-4) The compound according to any of (2-1) to (2-3) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (oxetanyl)C_1-4alkyl, [HO—((CH₂)_oO)_p]C_1-6alkyl, (C_1-6alkoxy)C_1-8alkyl optionally substituted with one or more hydroxy groups, C_1-3alkoxy substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (morpholino)C_1-6alkoxy optionally substituted with one or more oxo groups, (3- to 6-membered oxacycloalkyl)C_1-4alkoxy, (pyridinyl)C_1-4alkoxy, (pyrimidinyl)C_1-4alkoxy, (C_1-6alkoxy)C_1-8alkoxy optionally substituted with one or more hydroxy groups, (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl optionally substituted with one or more oxo groups, (3- to 6-membered oxacycloalkyl)C_2-6alkynyl, (pyrrolidino)C_2-6alkynyl optionally substituted with one or more oxo groups, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl optionally substituted with one or more hydroxy groups, (C_3-6cycloalkyl)C_2-6alkynyl optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, (morpholino)C_1-4alkylthio optionally substituted with one or more oxo groups, and 3- to 6-membered oxacycloalkyloxy.

(2-5) The compound according to any of (2-1) to (2-4) or a salt thereof, or a solvate of the compound or the salt, wherein each Ra is independently selected from a halogen atom, hydroxy, cyano, C_1-3alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy substituted with one or more hydroxy groups, (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, and (C_1-3alkoxy)carbonyl.

(2-6) The compound according to any of (2-1) to (2-5) or a salt thereof, or a solvate of the compound or the salt, wherein R³is methyl substituted with Re.

(2-7) The compound according to any of (2-1) to (2-6) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one or more substituents Ra on the benzene ring.

(2-8) The compound according to any of (2-1) to (2-7) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one to three substituents Ra on the benzene ring.

(2-9) The compound according to any of (2-1), (2-4) and (2-6) to (2-8) or a salt thereof, or a solvate of the compound or the salt, wherein Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom or C_1-3alkoxy;

Rj is a halogen atom, nitro, or cyano; and

Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C₂-10 alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², or C_1-4alkylthio optionally substituted with one or more substituents R¹³.

(2-10) The compound according to (2-9) or a salt thereof, or a solvate of the compound or the salt, wherein Rk is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl substituted with one or more hydroxy groups, C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy substituted with one or more hydroxy groups, (carboxy)C_2-8alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)carbonyl.

(2-11) The compound according to (2-1) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is a hydrogen atom or C_1-6alkyl;

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbonyl, (C_6-10aryl)carbonyl, —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

Re is C_6-10aryl optionally substituted with one or more substituents Ra;

each Ra is independently selected from a halogen atom, cyano, hydroxy, C_1-6alkyl optionally substituted with one or more substituents R¹⁰, C_2-6alkynyl optionally substituted with one or more substituents R¹, and C_1-6alkoxy optionally substituted with one or more substituents R¹²;

R¹⁰, R¹¹, and R¹²are each independently selected from 4- to 10-membered heterocycloalkyl optionally substituted with one or more substituents and a group —NR³⁹R⁴⁰, wherein the substituents are each independently selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups);

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb, Rc, and Rd are each independently selected from a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, optionally C_1-4alkyl-substituted 5- to 10-membered heterocycloalkyl, C_6-10aryl optionally substituted with one or more substituents R¹⁴, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy, a group —SO₂NR³⁵R³⁶, and C_1-4alkylthio.

(2-12) The compound according to (2-11) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰, R¹¹, and R¹²are each independently selected from 5- or 6-membered heterocycloalkyl optionally substituted with one or more substituents.

(2-13) The compound according to any of (2-1) and (2-11) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is C_1-6alkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom, optionally R¹¹-substituted C_2-6alkynyl, and optionally R¹²-substituted C_1-6alkoxy;

R¹¹and R¹²are each independently selected from 5- or 6-membered heterocycloalkyl and —NR³⁹R⁴⁰;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

(2-14) The compound according to any of (2-11) to (2-13) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

(2-15) The compound according to (2-13) or a salt thereof, or a solvate of the compound or the salt, wherein

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

R¹¹and R¹²are each independently selected from morpholinyl and a group —NR³⁹R⁴⁰;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl;

Ar¹is phenyl, pyridinyl, or pyrimidinyl, wherein the phenyl, pyridinyl, and pyrimidinyl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

(2-16) The compound according to (2-15) or a salt thereof, or a solvate of the compound or the salt, wherein R¹¹and R¹²are each independently selected from morpholinyl and [N-((methoxy)ethyl)-N-(methyl)amino].

(2-17) The compound according to (2-11) or (2-12) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰, R¹¹, and R¹²are each independently selected from morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, piperidyl, and [N-((methoxy)ethyl)-N-(methyl)amino].

(2-18) The compound according to any of (2-1) to (2-17) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom, and R⁴and R⁵are each independently selected from C_1-6alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-5saturated carbocyclic ring, and R⁴is C_1-6alkyl; and

(3) R¹is linear C_1-6alkyl, and

R⁴and R⁵together with the carbon atom to which they are attached form a pyrrolidine ring;

R³is benzyl substituted with one or more substituents Ra on the benzene ring;

each Ra is independently selected from a halogen atom, (morpholino)C_2-6alkoxy, (morpholino)C_1-6alkyl, (carboxy)C_2-6alkynyl, (C_1-6alkoxy)C_1-6alkoxy optionally substituted with one or more hydroxy groups, and [N-((methoxy)ethyl)-N-(methyl)amino]ethoxy;

Ar¹is phenyl or pyrimidyl, wherein these groups are each substituted with one to three groups each independently selected from a halogen atom, trifluoromethyl, pyridinyl substituted with one or more substituents R¹⁴, and pyrimidyl substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from methyl, cyano, trifluoromethyl, and methylthio.

(2-19) The compound according to any of (2-1) to (2-18) or a salt thereof, or a solvate of the compound or the salt, wherein Ar¹is 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.

(2-20) The compound according to any of (2-1) to (2-19) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring;

R⁴is C_1-4alkyl;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom and C_1-4alkoxy optionally substituted with one or more substituents R¹²;

each R¹²is independently selected from 5- or 6-membered heterocycloalkyl and a group —NR³⁹R⁴⁰;

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-4alkoxy-substituted C_1-4alkyl;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, and C_1-4alkylthio.

(2-21) The compound according to (2-20) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is selected from a halogen atom and 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(2-22) The compound according to any of (2-1), (2-20) and (2-21) or a salt thereof, or a solvate of the compound or the salt, wherein

Re is phenyl optionally substituted with one to three substituents Ra;

Ri and Rj are each independently a halogen atom; and

Rk is C_1-4alkoxy optionally substituted with one or more substituents R¹².

(2-23) The compound according to any of (2-20) to (2-22) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl, wherein the benzyl group is optionally substituted with one to three substituents Ra.

(2-24) The compound according to any of (2-20) to (2-23) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is phenyl or pyridinyl;

Rd is pyridinyl or pyrimidinyl; and

R¹²is morpholinyl or [N-((methoxy)ethyl)-N-(methyl)amino].

(2-25) The compound according to any of (2-1) to (2-24) or a salt thereof, or a solvate of the compound or the salt, wherein the compound is represented by the formula I-a:

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wherein q is an integer selected from 0 to 3, and R³, R⁴, and Ar¹are as defined above in any of (2-1) to (2-24).

(2-26) A compound selected from:

(4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrlo[1,2-b]pyridazine-3-carboxamide;
(4aR)—N-[2-(6-cyano-5-methylpyrimidin-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;
(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-ynoic 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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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-morpholin-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-morpholin-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-morpholin-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-pyridazine-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-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-[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; and
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 salt thereof, or a solvate of the compound or the salt.

Another embodiment of the present invention provides the following compounds (3-1) to (3-13):

(3-1) A compound represented by the formula (I) or a salt thereof or a solvate of the compound or the salt:

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wherein

R¹is a hydrogen atom or C_1-10alkyl;

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbonyl, (C_6-10aryl)carbonyl, —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl;

R⁵is a hydrogen atom or C_1-4alkyl; or

R¹and R⁵together with the carbon atom to which they are attached may form a C_3-6saturated carbocyclic ring; or

R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached may form a 5- to 8-membered saturated heterocyclic ring, wherein the 5- to 8-membered saturated heterocyclic ring is optionally substituted with one or more substituents R²;

R³is C_1-10alkyl optionally substituted with one or more substituents Rh, or C_1-4alkyl substituted with Re;

R³⁷and R³⁸are each independently selected from a hydrogen atom and C_1-3alkyl;

each R²is independently selected from C_1-5alkyl and a halogen atom; and/or

two or more substituents R²on the 5- to 8-membered saturated heterocyclic ring may together form C_1-5alkylene that links the ring atoms to which they are attached;

each Rh is independently selected from a halogen atom, (C_1-4alkoxy)carbonyl, and —(O(CH₂)_a)_b—C_1-4alkoxy (wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4);

Re is C_6-10aryl optionally substituted with one or more substituents Ra or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;

each Rf is independently selected from a halogen atom, hydroxy, cyano, carboxy, (C_1-6alkoxy)carbonyl, C_1-6alkoxy, and C_6-10aryl optionally substituted with one or more substituents Rg;

each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

the substituents R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with one or more substituents selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups);

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

each R¹⁴is independently selected from a halogen atom, oxo, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, —NR²⁷R²⁸, —SO₂NR³⁵R³⁶, C_1-4alkylthio, and 5- to 10-membered heterocycloalkyl;

R²⁷and R²⁸are each independently selected from a hydrogen atom and optionally (C_1-4alkoxy)carbonyl-substituted C_1-4alkyl; and

R³⁵and R³⁶are each independently selected from a hydrogen atom and C_1-4alkyl.

(3-2) The compound according to (3-1) or a salt thereof, or a solvate of the compound or the salt, wherein R¹is C_1-10alkyl.

(3-3) The compound according to (3-1) or (3-2) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom;

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and

Rd is selected from cyano, hydroxy, a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(3-4) The compound according to any of (3-1) to (3-3) or a salt thereof, or a solvate of the compound or the salt, wherein

each Ra is independently selected from a halogen atom, nitro, cyano, (C_1-4alkoxy)carbonyl, 5- or 6-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from carboxy, 5- or 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

each R¹²is independently selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 5- or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

each R¹³is independently selected from 5- or 6-membered heterocycloalkyl; and o and p are each independently an integer selected from 2 to 4.

(3-5) The compound according to any of (3-1) to (3-4) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is selected from C_1-4alkyl;

R³is selected from C_1-4alkyl substituted with Re;

Re is selected from C_6-10aryl optionally substituted with one or more substituents Ra;

each Ra is independently selected from a halogen atom and optionally R¹²-substituted C_1-6alkoxy;

R⁴is selected from C_1-4alkyl;

R⁵is selected from C_1-4alkyl; or

of R¹, R⁴, and R⁵, R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring, or R⁴and R⁵together with the nitrogen atom and the carbon atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring;

Ar¹is C_6-10aryl, wherein the aryl group is substituted with two substituents selected from Rc and Rd;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms;

Rd is 5- to 10-membered heterocycloalkyl optionally substituted with one or more C_1-4alkyl groups and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴;

R¹²is 5- to 10-membered heterocycloalkyl; and

R¹⁴is C_1-4alkyl optionally substituted with one or more halogen atoms.

(3-6) The compound according to (3-1) or (3-2) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is a hydrogen atom or C_1-6alkyl;

R³is C_1-4alkyl substituted with Re;

Re is C_6-10aryl optionally substituted with one or more substituents Ra; each Ra is independently selected from a halogen atom, cyano, hydroxy, C_1-6alkyl optionally substituted with one or more substituents R¹⁰, C_2-6alkynyl optionally substituted with one or more substituents R¹¹, and C_1-6alkoxy optionally substituted with one or more substituents R¹²;

R¹⁰, R¹¹, and R¹²are each independently selected from 4- to 10-membered heterocycloalkyl optionally substituted with one or more substituents, wherein the substituents are each independently selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups);

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbonyl, (C_6-10aryl)carbonyl, —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl;

R⁵is a hydrogen atom or C_1-4alkyl; or

R¹and R⁵together with the carbon atom to which they are attached may form a C_3-6saturated carbocyclic ring;

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy, —SO₂NR³⁵R³⁶, and C_1-4alkylthio.

(3-7) The compound according to any of (3-1), (3-2), and (3-6) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is C_1-6alkyl;

R³is C_1-4alkyl substituted with Re;

Re is C_6-10aryl optionally substituted with one or more substituents Ra;

each Ra is independently selected from a halogen atom, optionally R¹¹-substituted C_2-6alkynyl, and optionally R¹²-substituted C_1-6alkoxy;

R¹¹and R¹²are each independently selected from 5- to 10-membered heterocycloalkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or C_6-10aryl;

R⁵is a hydrogen atom or C_1-4alkyl; or

R¹and R⁵together with the carbon atom to which they are attached may form a C_3-6saturated carbocyclic ring;

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb, Rc, and Rd are each independently selected from a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, C_6-10aryl optionally substituted with one or more substituents R¹⁴, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy, —SO₂NR³⁵R³⁶(wherein R³⁵and R³⁶are each independently selected from C_1-4alkyl), and C_1-4alkylthio.

(3-8) The compound according to (3-7) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, C_6-10aryl optionally substituted with one or more substituents R¹⁴, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(3-9) The compound according to (3-7) or a salt thereof, or a solvate of the compound or the salt, wherein

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

R¹¹and R¹²are each independently morpholinyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl;

Ar¹is phenyl, pyridinyl, or pyrimidinyl, wherein the phenyl, pyridinyl, and pyrimidinyl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

(3-10) The compound according to (3-6) or (3-7) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰, R¹¹, and R¹²are each independently selected from morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, piperazinyl, and piperidyl.

(3-11) The compound according to any of (3-1) to (3-10) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one or more substituents Ra on the benzene ring.

(3-12) The compound according to (3-1) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is C_1-6alkyl, and R⁴and R⁵together with the carbon atom to which they are attached form a pyrrolidine ring; or

R¹is a hydrogen atom, and R⁴and R⁵are each independently selected from C_1-6alkyl; or

R¹and R⁵together with the carbon atom to which they are attached form a C_3-5saturated carbocyclic ring, and R⁴is C_1-6alkyl;

R³is benzyl substituted with one or more substituents Ra on the benzene ring;

each Ra is independently selected from a halogen atom, (morpholino)C_2-6alkoxy, (morpholino)C_1-6alkyl, (carboxy)C_2-6alkynyl, and (C_1-6alkoxy)C_1-6alkoxy optionally substituted with one or more hydroxy groups;

each R¹⁴is independently selected from methyl, cyano, trifluoromethyl, and methylthio.

(3-13) The compound according to any of (3-1) to (3-11) or a salt thereof, or a solvate of the compound or the salt, wherein Ar¹is 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.

An alternative aspect of the present invention provides a pharmaceutical drug comprising a compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides a pharmaceutical composition comprising a compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides the compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or the salt thereof, or the solvate of the compound or the salt for use in the prevention and/or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure.

A further alternative aspect of the present invention provides a NaPi-IIb inhibitor comprising a compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides a preventive and/or therapeutic agent for a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, the agent comprising a compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or a salt thereof, or a solvate of the compound or the salt as an active ingredient.

A further alternative aspect of the present invention provides a method for preventing and/or treating a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, comprising administering a therapeutically effective amount of a compound according to any of (2-1) to (2-26) and (3-1) to (3-13) or a salt thereof, or a solvate of the compound or the salt to a patient.

According to one embodiment of the compound represented by the formula (I) wherein R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring, the following compound (4-1) is provided:

(4-1) A compound represented by the formula (II) or a salt thereof, or a solvate of the compound or the salt:

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wherein R¹⁰is selected from a hydrogen atom and linear C_1-10alkyl;

R¹⁰²may be the same or different and are each independently selected from a hydrogen atom, C_1-5alkyl, and a halogen atom; or

two R¹⁰²moieties bonded to different carbon atoms may together form C_1-5alkylene that links the carbon atoms;

R^102′may be the same or different and are each independently selected from a hydrogen atom, C_1-5alkyl, and a halogen atom;

n is an integer selected from 1 to 4;

R¹⁰³is C_1-10alkyl optionally substituted with one or more substituents Rw or C_1-4alkyl substituted with one or more substituents Rx;

each Rw is independently selected from a halogen atom, (C_1-4alkoxy)carbonyl, and a group —(O(CH₂)_a)_b—C_1-4alkoxy (wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4);

each Rx is independently selected from C_6-10aryl optionally substituted with one or more substituents Ry and 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ry;

each Ry is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 5- to 10-membered heterocycloalkyl optionally substituted with one or more oxo groups, and 5- to 10-membered heteroaryl;

Ar¹⁰¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the C_6-10aryl and 5- to 10-membered heteroaryl groups are each optionally substituted with one to three substituents selected from Rz¹, Rz², and Rz³;

Rz¹, Rz², and Rz³are each independently selected from optionally C_1-4alkoxy-substituted C_1-5alkoxy, a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, a group —SF₅, cyano, hydroxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹¹⁴, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹¹⁴; and

each R¹¹⁴is independently selected from a halogen atom, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, a group —NR¹²⁷R¹²⁸(wherein R¹²⁷and R¹²⁸are each independently selected from a hydrogen atom and optionally (C_1-4alkoxy)carbonyl-substituted C_1-4alkyl), a group —SO₂NR¹³⁵R¹³⁶(wherein R¹³⁵and R¹³⁶are each independently selected from a hydrogen atom and C_1-4alkyl), C_1-4alkylthio, and 5- to 10-membered heterocycloalkyl.

According to another embodiment, the present invention provides the following compounds (4-2) to (4-17) represented by the formula (II).

(4-2) The compound according to (4-1) or a salt thereof, or a solvate of the compound or the salt, wherein

Rz¹is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom;

Rz²is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, and a group —SF₅; and

Rz³is cyano, hydroxy, a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹¹⁴or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹¹⁴.

(4-3) The compound according to (4-1) or (4-2) or a salt thereof, or a solvate of the compound or the salt, wherein Rz³is cyano, hydroxy, a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, phenyl, and 5- to 6-membered heteroaryl, wherein the pheny and 5- to 6-membered heteroaryl may be substituted with one or two substituents R¹¹⁴.

(4-4) The compound according to any of (4-1) to (4-3) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹⁰¹is a hydrogen atom or linear C_1-6alkyl;

R¹⁰²may be the same or different and are each independently selected from a hydrogen atom, C_1-3alkyl, and a halogen atom;

R^102′may be the same or different and are each independently selected from a hydrogen atom, C_1-3alkyl, and a halogen atom;

n is an integer selected from 1 to 3;

Rx is independently selected from C_6-10aryl optionally substituted with one or more substituents Ry and 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ry;

Ry is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-3alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹¹², and C_1-3alkylthio optionally substituted with one or more substituents R¹¹³;

R¹¹⁰is independently selected from carboxyl, 5- to 10-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4);

R¹¹¹is independently selected from hydroxy, carboxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), and C_3-6cycloalkyl optionally substituted with one or more hydroxy groups;

R¹¹²is independently selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 5- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl;

R¹¹³is independently selected from 5- to 10-membered heterocycloalkyl;

Rz¹is selected from optionally C_1-3alkoxy-substituted C_1-4alkoxy and a halogen atom; and

R¹¹⁴is independently selected from a halogen atom, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, a group —NR¹²⁷R¹²⁸(wherein R¹²⁷and R¹²⁸are each independently selected from a hydrogen atom and optionally (C_1-3alkoxy)carbonyl-substituted C_1-4alkyl), a group —SO₂NR¹³⁵R¹³⁶(wherein R¹³⁵and R¹³⁶are each independently selected from a hydrogen atom and C_1-3alkyl), C_1-3alkylthio, and 5- to 10-membered heterocycloalkyl.

(4-5) The compound according to any of (4-1) to (4-4) or a salt thereof, or a solvate of the compound or the salt, wherein Rx is C_6-10aryl optionally substituted with one or more substituents Ry.

(4-6) The compound according to any of (4-1) to (4-5) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹⁰¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with Rz¹, Rz², and/or Rz³;

Rz¹is a halogen atom or optionally C_1-3alkoxy-substituted C_1-4alkoxy;

Rz²is a halogen atom or C_1-10alkyl optionally substituted with one or more halogen atoms; and

Rz³is 5- or 6-membered heterocycloalkyl optionally substituted with one or more substituents R¹¹⁴, phenyl optionally substituted with one or more substituents R¹¹⁴, or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹¹⁴.

(4-7) The compound according to any of (4-1) to (4-6) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹⁰¹is phenyl or 5- or 6-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rz¹, Rz², and Rz³;

Rz¹is a halogen atom;

Rz²is selected from a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, and a group —SF₅; and

Rz³is cyano, hydroxy, or a halogen atom.

(4-8) The compound according to any of (4-1) to (4-7) or a salt thereof, or a solvate of the compound or the salt, wherein Rz³is phenyl, thienyl, pyridinyl, pyrimidinyl, or quinolinyl, wherein these groups are each optionally substituted with one or more substituents R¹¹⁴.

(4-9) The compound according to any of (4-1) to (4-8) or a salt thereof, or a solvate of the compound or the salt, wherein each R¹¹⁴is independently selected from a halogen atom, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, a group —NR¹²⁷R¹²⁸(each R¹²⁷and R¹²⁸are independently selected from a hydrogen atom, and C_1-4alkyl optionally substituted with (C_1-4alkoxy)carbonyl), a group —SO₂NR¹³⁵R¹³⁶(each R¹³⁵and R¹³⁶are independently selected from a hydrogen atom, and C_1-4alkyl), and C_1-4alkylthio.

(4-10) The compound according to any of (4-1) to (4-9) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰¹is linear C_1-6alkyl.

(4-11) The compound according to any of (4-1) to (4-10) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰²and R^102′ are a hydrogen atom.

(4-12) The compound according to any of (4-1) to (4-11) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹⁰¹is linear C_1-6alkyl;

R¹⁰²and R^102′ are a hydrogen atom;

R¹⁰³is C_1-10alkyl optionally substituted with Rx;

Rx is phenyl optionally substituted with one or more substituents Ry;

each Ry is independently selected from a halogen atom and C_1-8alkoxy optionally substituted with R¹¹²;

R¹¹²is 5- or 6-membered heterocycloalkyl;

Ar¹⁰¹is phenyl optionally substituted with one to three substituents selected from Rz¹, Rz², and Rz³;

Rz¹is optionally C_1-3alkoxy-substituted C_1-4alkoxy or a halogen atom;

Rz²is a halogen atom or C_1-10alkyl optionally substituted with one or more halogen atoms;

Rz³is 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹¹⁴; and

each R¹¹⁴is selected independently from C_1-4alkyl optionally substituted with one or more halogen atoms.

(4-13) The compound according to any of (4-1) to (4-12) or a salt thereof, or a solvate of the compound or the salt, wherein Rz³is substituted with one or two substituents R¹¹⁴.

(4-14) The compound according to any of (4-1) to (4-13) or a salt thereof, or a solvate of the compound or the salt, wherein R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, and R¹¹⁵are each independently selected from tetrahydrofuranyl, pyrrolidinyl, morpholinyl, cyclopentyl, and pyridinyl.

(4-15) The compound according to any of (4-1) to (4-14) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰³is benzyl optionally substituted with one or more substituents Ry on the benzene ring.

(4-16) The compound according to any of (4-1) to (4-15) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰³is benzyl optionally substituted with one to three substituents Ry on the benzene ring.

(4-17) The compound according to any of (4-1) to (4-16) or a salt thereof, or a solvate of the compound or the salt, wherein the one to three substituents Ry are one substituent selected from Ri′, Rj′, and Rk′, two substituents selected from combinations of Ri′ and Rj′, R′i and Rk′, and Rj′ and Rk′, or three substituents Ri′, Rj′, and Rk′;

Ri′ is a halogen atom or C_1-3alkoxy;

Rj′ is a halogen atom, nitro, or cyano; and

Rk′ is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (C_1-6alkoxy)C_1-8alkyl, (the alkoxy is optionally substituted with one or more hydrxy groups), (5- to 6-membered heterocycloalkyl)C_1-6alkoxy, [HO—((CH₂)_oO)_p]C_1-6alkyl, (carboxy)C_2-6alkynyl, (3- to 6-membered heterocycloalkyl)C_2-6alkynyl (the heterocycloalkyl moiety is optionally substituted with oxo), C_1-3alkoxy optionally substituted with one or more halogen atoms, C_1-6alkoxy substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (pyridinyl)C_1-4alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), optionally hydroxy-substituted C_2-8alkynyl, (C_3-6cycloalkyl)C_2-6alkynyl (the cycloalkyl is optionally substituted with a hydroxy group), [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is optionally substituted with one or more hydroxy groups), (morpholino)C_1-4alkylthio, 3- to 6-membered oxacycloalkyloxy, or (C_1-3alkoxy)carbonyl.

An alternative embodiment of the present invention provides the following compounds (5-1) to (5-12) represented by the formula (I):

(5-1) The compound according to (1-1), (2-1) or (3-1) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is a hydrogen atom or linear C_1-10alkyl; and

(5-2) The compound according to (5-1) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom; and/or

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and/or

(5-3) The compound according to (5-1) or (5-2) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is a hydrogen atom or linear C_1-6alkyl;

R²may be the same or different and are each independently selected from C_1-3alkyl and a halogen atom;

Re is C_6-10aryl optionally substituted with one or more substituents Ra or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;

each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-3alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-3alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from carboxyl, 5- to 10-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4);

each R¹¹is independently selected from hydroxy, carboxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), and C_3-6cycloalkyl optionally substituted with one or more hydroxy groups;

each R¹²is selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 5- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl;

each R¹³is independently selected from 5- to 10-membered heterocycloalkyl;

Rb is optionally C_1-3alkoxy-substituted C_1-4alkoxy or a halogen atom; and

each R¹⁴is independently selected from a halogen atom, cyano, nitro, C_1-4alkyl optionally substituted with one or more halogen atoms, C_1-4alkoxy optionally substituted with one or more halogen atoms, (C_1-6alkoxy)carbonyl, a group —NR²⁷R²⁸(wherein R²⁷and R²⁸are each independently selected from a hydrogen atom and optionally (C_1-3alkoxy)carbonyl-substituted C_1-4alkyl), a group —SO₂NR³⁵R³⁶(wherein R³⁵and R³⁶are each independently selected from a hydrogen atom and C_1-3alkyl), C_1-3alkylthio, and 5- to 10-membered heterocycloalkyl.

(5-4) The compound according to any of (5-1) to (5-3) or a salt thereof, or a solvate of the compound or the salt, wherein Re is selected from C_6-10aryl optionally substituted with one or more substituents Ra.

(5-5) The compound according to any of (5-1) to (5-4) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with Rb, Rc, and/or Rd;

Rb is a halogen atom or optionally C_1-3alkoxy-substituted C_1-4alkoxy; and/or

Rc is a halogen atom or C_1-10alkyl optionally substituted with one or more halogen atoms; and/or

Rd is 5- or 6-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, phenyl optionally substituted with one or more substituents R¹⁴, or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(5-6) The compound according to any of (5-1) to (5-5) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is a halogen atom;

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and

Rd is cyano, hydroxy, or a halogen atom.

(5-7) The compound according to any of (5-1) to (5-6) or a salt thereof, or a solvate of the compound or the salt, wherein Rd is phenyl, thienyl, pyridinyl, pyrimidinyl, or quinolinyl, wherein these groups are each optionally substituted with one or more substituents R¹⁴.

(5-8) The compound according to any of (5-1) to (5-7) or a salt thereof, or a solvate of the compound or the salt, wherein R¹is linear C_1-6alkyl.

(5-9) The compound according to any of (5-1) to (5-8) or a salt thereof, or a solvate of the compound or the salt, wherein R²is a hydrogen atom.

(5-10) The compound according to any of (5-1) to (5-9) or a salt thereof, or a solvate of the compound or the salt, wherein

R¹is linear C_1-6alkyl;

R²is a hydrogen atom;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom and optionally R¹²-substituted C_1-8alkoxy;

each R¹²is independently selected from 5- or 6-membered heterocycloalkyl;

Ar¹is phenyl optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is optionally C_1-3alkoxy-substituted C_1-4alkoxy and a halogen atom; and/or

Rc is a halogen atom or C_1-10alkyl optionally substituted with one or more halogen atoms; and/or

Rd is 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴; and

each R¹⁴is independently selected from C_1-4alkyl optionally substituted with one or more halogen atoms.

(5-11) The compound according to any of (5-1) to (5-10) or a salt thereof, or a solvate of the compound or the salt, wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from tetrahydrofuranyl, pyrrolidinyl, morpholinyl, cyclopentyl, and pyridinyl.

(5-12) The compound according to any of (5-1) to (5-11) or a salt thereof, or a solvate of the compound or the salt, wherein R³is benzyl optionally substituted with one or more substituents Ra on the benzene ring.

An alternative embodiment of the present invention provides the following compounds (6-1) to (6-10) represented by the formula (I):

(6-1) A compound represented by the formula I-b or a salt thereof, or a solvate of the compound or the salt:

embedded image

wherein

R^4′ is selected from C_1-4alkyl;

q is an integer selected from 0 to 3;

R^3′ is selected from C_1-4alkyl substituted with Re′;

Re′ is C_6-10aryl, wherein the aryl group is optionally substituted with one to three substituents each independently selected from a halogen atom, C_1-4alkoxy optionally substituted with one or more substituents R^12′, 4- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), a group —(O(CH₂)_q1)_q2—NR^41′R^42′ (wherein q1 is an integer selected from 1 to 4, and q2 is an integer selected from 2 to 6), a group —(O(CH₂)_r1)_r2—C(O)NR^43′R^44′ (wherein r1 is an integer selected from 1 to 4, and r2 is an integer selected from 1 to 4), a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶(wherein s1 and s2 are each independently an integer selected from 2 to 4), a group —C(O)NR^47′R^48′, pyridinyl, pyrrolyl, a group —NR^49′R^50′and a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR^51′R^52′ (wherein y1 is an integer selected from 1 to 4, and y2 is an integer selected from 1 to 4);

each R^12′ is independently selected from (C_1-4alkoxy)C_1-6alkoxy, 5- or 6-membered heterocycloalkyl, and a group —NR^39′R^40′, wherein the 5- or 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, C_1-4alkoxycarbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and —C(O)NR^53′R^54′;

R^39′ is selected from a hydrogen and optionally C_1-6alkoxy-substituted C_1-6alkyl;

R^40′ is independently selected from a hydrogen atom, optionally C_1-6alkoxy-substituted C_1-6alkyl, ((C_1-4alkoxy)carbonyl)C_1-6alkyl, hydroxy-substituted C_1-6alkyl, a group —(CH₂)_u—NR^55′R^56′ (wherein u is an integer selected from 1 to 4), a group —CH((CH₂)_v1COOR^57′)—(CH₂)_v2—COOR^57′ (wherein v1 is an integer selected from 0 to 2, and v2 is an integer selected from 1 to 3), a group —(CH₂)_w—SO₃H (wherein w is an integer selected from 1 to 4), a group —(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H (wherein x1 is an integer selected from 0 to 2, and x2 is an integer selected from 1 to 3), 3- to 6-membered oxacycloalkyl, and a group —(CH₂)_t1—O—(CH₂)_t2—C(O)NR^58′R^59′ (wherein t1 and t2 are each independently an integer selected from 1 to 3);

R^41′ is a hydrogen atom or C_1-3alkyl;

R^42′ is C_1-8alkyl substituted with one or more hydroxy groups or (C_1-3alkoxy)C_1-4alkyl:

R^43′ is a hydrogen atom or C_1-3alkyl;

R^44′ is C_1-8alkyl substituted with one or more hydroxy groups, wherein

R^43′ and R^44′ together with the nitrogen atom to which they are attached may form morpholino;

R^45′ is a hydrogen atom and C_1-3alkyl;

R^46′ is C_1-6alkyl substituted with one or more hydroxy groups;

R^47′ is C_1-3alkyl;

R^48′ is (C_1-3alkoxy)C_1-4alkyl;

R^49′ is a hydrogen atom or C_1-4alkyl;

R^50′ is —(CH₂)_z—NR^60′R^61′ (z is an integer selected from 1 to 4, R^60′ is a hydrogen atom and C_1-4alkyl, and R^61′ is (C_1-3alkoxy)C_1-4alkyl, or R^60′ and R^61′ together with the nitrogen atom to which they are attached may form morpholino);

R^51′ is a hydrogen atom and C_1-4alkyl;

R^52′ is C_1-8alkyl substituted with one or more hydroxy groups;

R^53′ and R^54′ are each independently selected from a hydrogen atom and C_1-4alkyl;

R^55′ is a hydrogen atom or C_1-4alkyl;

R^56′ is (C_1-4alkyl)carbonyl;

R^57′ is a hydrogen atom or C_1-4alkyl;

R^58′ is a hydrogen atom or C_1-3alkyl;

R^59′ is C_1-8alkyl substituted with one or more hydroxy groups;

Ar²is phenyl or 5- or 6-membered heteroaryl, wherein the aryl and the heteroaryl groups are each optionally substituted with one to three substituents selected from Rb′, Rc′, and Rd′;

Rb′, Rc′, and Rd′ are each independently selected from optionally C_1-4alkoxy-substituted C_1-5alkoxy, a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, and 5- or 6-membered heteroaryl optionally substituted with one or more substituents R^14′; and

each R^14′ is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, and C_1-4alkylthio.

(6-2) The compound according to (6-1) or a salt thereof, or a solvate of the compound or the salt, wherein

R^4′ is C_1-4alkyl;

q is an integer selected from 0 to 3;

R^3′ is C_1-4alkyl substituted with Re′;

Re′ is C_6-10aryl, wherein the aryl group is optionally substituted with one to three substituents each independently selected from a halogen atom and C_1-4alkoxy optionally substituted with one or more substituents R^12′;

each R^12′ is independently selected from 5- or 6-membered heterocycloalkyl and a group —NR^39′R^40′;

R^39′ and R^40′ are each independently selected from a hydrogen atom and optionally C_1-4alkoxy-substituted C_1-4alkyl;

Ar²is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb′, Rc′, and Rd′;

Rb′, Rc′, and Rd′ are each independently selected from a halogen atom, C_1-4alkyl optionally substituted with one or more halogen atoms, and 5- or 6-membered heteroaryl optionally substituted with one or more substituents R^14′; and

each R^14′ is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, and C_1-4alkylthio.

(6-3) The compound according to (6-1) or (6-2) or a salt thereof, or a solvate of the compound or the salt, wherein

Rb′ is a halogen atom;

Rc′ is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd′ is a halogen atom or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R^14′.

(6-4) The compound according to any of (6-1) to (6-3) or a salt thereof, or a solvate of the compound or the salt, wherein R^3′ is benzyl, wherein phenyl in the benzyl group is optionally substituted with one to three substituents each independently selected from a halogen atom and C_1-4alkoxy optionally substituted with one or more substituents R^12′.

(6-5) The compound according to any of (6-1) to (6-4) or a salt thereof, or a solvate of the compound or the salt, wherein Re′ is phenyl, wherein the phenyl group is optionally substituted with 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′ are each independently a halogen atom; and

Rk′ is C_1-4alkoxy optionally substituted with one or more substituents R¹².

(6-6) The compound according to any of (6-1) to (6-5) or a salt thereof, or a solvate of the compound or the salt, wherein

Ar²is phenyl or pyridinyl;

Rd′ is pyridinyl or pyrimidinyl; and

R^12′ is morpholinyl or —NR^39′R^40′.

(6-7) The compound according to any of (6-1) to (6-6) or a salt thereof, or a solvate of the compound or the salt, wherein R^12′ is selected from morpholinyl, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino], and [N,N-di(C_1-3alkyl)amino].

(6-8) The compound according to any of (6-1) to (6-3) or a salt thereof, or a solvate of the compound or the salt, wherein Ra is selected from a halogen atom, (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, and [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(6-9) The compound according to (6-5) or (6-6) or a salt thereof, or a solvate of the compound or the salt, wherein Rk is selected from (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, and [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(6-10) The compound according to any of (6-1) to (6-6) or a salt thereof, or a solvate of the compound or the salt, wherein R^12′ is a group —NR^39′R^40′.

An alternative aspect of the present invention provides a pharmaceutical drug comprising a compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides a pharmaceutical composition comprising a compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides the compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or the salt thereof, or the solvate of the compound or the salt for use in the prevention and/or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure.

A further alternative aspect of the present invention provides a NaPi-IIb inhibitor comprising a compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or a salt thereof, or a solvate of the compound or the salt.

A further alternative aspect of the present invention provides a preventive and/or therapeutic agent for a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, the agent comprising a compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or a salt thereof, or a solvate of the compound or the salt as an active ingredient.

A further alternative aspect of the present invention provides a method for preventing and/or treating a disease selected from hyperphosphatemia, secondary hyperparathyroidism, and chronic renal failure, comprising administering a therapeutically effective amount of a compound according to any of (4-1) to (4-17), (5-1) to (5-12), and (6-1) to (6-10) or a salt thereof, or a solvate of the compound or the salt to a patient.

The present inventors have further found for the first time that a compound represented by the formula (I) has an excellent NaPi-IIb inhibitory effect, PiT-1 inhibitory effect, or PiT-2 inhibitory effect, that the compound is useful in the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification and in the prevention or suppression of ectipic calcification, and that the compound has excellent drug efficacy on these diseases.

Further, the inventors have found for the first time that inhibition of one or more transporters selected from PiT-1 and PiT-2 provides an excellent effect in the prevention or treatment of hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification (herein after referred to as “hyperphosphatemia, etc.”) and in the prevention or suppression of ectipic calcification.

Furthermore, the inventors have found that use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 in combination with a phosphorus adsorbent provides an excellent effect in the prevention or treatment of hyperphosphatemia, etc. and in the prevention or suppression of ectipic calcification, and completed the present invention.

One aspect of the present invention provides the following pharmaceutical compositions (7-1) to (7-60).

(7-1) A pharmaceutical composition comprising a compound represented by the formula (I) or a salt thereof, or a solvate of the compound or the salt:

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wherein R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom or C_1-10alkyl;

R⁴is a hydrogen atom, C_1-4alkyl optionally substituted with one or more substituents Rf, C_6-10aryl optionally substituted with one or more substituents Rg, (C_1-6alkyl)carbonyl, (C_6-10aryl)carbonyl, a group —C(O)NR³⁷R³⁸, C_3-7cycloalkyl, or 5- to 8-membered heterocycloalkyl; and

R⁵is a hydrogen atom or C_1-4alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above; and

(3) R¹is a hydrogen atom or linear C_1-10alkyl;

R³is C_1-10alkyl optionally substituted with one or more substituents Rh, or R³is C_1-4alkyl substituted with Re;

R³⁷and R³⁸are each independently selected from a hydrogen atom and C_1-3alkyl;

each R²is independently selected from C_1-5alkyl and a halogen atom; and/or

two or more substituents R²on the 5- to 8-membered saturated heterocyclic ring may together form C_1-5alkylene that links the ring atoms to which they are attached;

Re is C_6-10aryl optionally substituted with one or more substituents Ra, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;

each Rf is independently selected from a halogen atom, hydroxy, cyano, carboxy, (C_1-6alkoxy)carbonyl, C_1-6alkoxy, and C_6-10aryl optionally substituted with one or more substituents Rg;

each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴²(wherein q1 is an integer selected from 1 to 4, and q2 is an integer selected from 2 to 6), a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴(wherein r1 is an integer selected from 1 to 4, and r2 is an integer selected from 1 to 4), a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶(wherein s1 and s2 are each independently an integer selected from 2 to 4), a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²(wherein yl is an integer selected from 1 to 4, and y2 is an integer selected from 1 to 4);

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

R²⁷and R²⁸are each independently selected from a hydrogen atom and C_1-4alkyl optionally substituted with (C_1-4alkoxy)carbonyl;

R³⁵and R³⁶are each independently selected from a hydrogen atom and C_1-4alkyl;

R³⁹is a hydrogen atom or C_1-6alkyl, wherein the alkyl is optionally substituted with hydroxy or C_1-6alkoxy;

R⁴⁰is a hydrogen atom, optionally C_1-6alkoxy-substituted C_1-6alkyl, ((C_1-4alkoxy)carbonyl)C_1-6alkyl, hydroxy-substituted C_1-6alkyl, C_1-4alkyl substituted with a group —NR⁵⁵R⁵⁶, a group —CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷(wherein v1 is an integer selected from 0 to 2, and v2 is an integer selected from 1 to 3), a group —(CH₂)_w—SO₃H (wherein w is an integer selected from 1 to 4), a group —(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H (wherein x1 is an integer selected from 0 to 2, and x2 is an integer selected from 1 to 3), 3- to 6-membered oxacycloalkyl, or a group —(CH₂)_t1—O—(CH₂)_t2—C(O)NR⁵⁸R⁵⁹(wherein t1 and t2 are each independently an integer selected from 1 to 3);

R⁴¹is a hydrogen atom or C_1-3alkyl;

R⁴²is C_1-8alkyl substituted with one or more hydroxy groups, or (C_1-3alkoxy)C_1-4alkyl;

R⁴³is a hydrogen atom or C_1-3alkyl;

R⁴⁴is C_1-8alkyl substituted with one or more hydroxy groups, or

R⁴³and R⁴⁴together with the nitrogen atom to which they are attached may form morpholino;

R⁴⁵is a hydrogen atom or C_1-3alkyl;

R⁴⁶is C_1-6alkyl substituted with one or more hydroxy groups;

R⁴⁷is C_1-3alkyl;

R⁴⁸is (C_1-3alkoxy)C_1-4alkyl;

R⁴⁹is a hydrogen atom and C_1-4alkyl;

R⁵⁰is —(CH₂)_z—NR⁶⁰R⁶¹(wherein z is an integer selected from 1 to 4, R⁶⁰is a hydrogen atom or C_1-4alkyl, and R⁶¹is (C_1-3alkoxy)C_1-4alkyl, or R⁶⁰and R⁶¹together with the nitrogen atom to which they are attached may form morpholino);

R⁵¹is a hydrogen atom or C_1-4alkyl;

R⁵²is C_1-8alkyl substituted with one or more hydroxy groups;

R⁵³and R⁵⁴are each independently selected from a hydrogen atom and C_1-4alkyl;

R⁵⁵is a hydrogen atom or C_1-4alkyl;

R⁵⁶is (C_1-4alkyl)carbonyl;

R⁵⁷is a hydrogen atom or C_1-4alkyl;

R⁵⁸is a hydrogen atom or C_1-3alkyl; and

R⁵⁹is C_1-8alkyl substituted with one or more hydroxy groups.

(7-2) The pharmaceutical composition of (7-1), wherein, in the compound represented by the formula (I), Rb is optionally C_1-4alkoxy-substituted C_1-5alkoxy or a halogen atom;

Rc is a halogen atom, C_1-10alkyl optionally substituted with one or more halogen atoms, or a group —SF₅; and

(7-3) The pharmaceutical composition of (7-2) or (7-3), wherein, in the compound

represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

R¹⁰, R¹¹, R¹², R¹³, and R¹⁵are each independently selected from a halogen atom, hydroxy, carboxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-4alkoxy)carbonyl, a group —(O(CH₂)_o)_p—OH (wherein o and p are each independently an integer selected from 2 to 4), C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR³⁹R⁴⁰, wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, and C_1-4alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups); and

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-6alkoxy-substituted C_1-6alkyl.

(7-4) The pharmaceutical composition of any of (7-1) to (7-3), wherein, in the compound represented by the formula (I), 3- to 10-membered heterocycloalkyloxy in the definition of Ra is 3- to 6-membered heterocycloalkyloxy;

3- to 10-membered heterocycloalkyl in the definition of R¹⁰, R¹¹, R¹², R¹³and R¹⁵is 3- to 6-membered heterocycloalkyl; and

5- to 10-membered heteroaryl in the definition of R¹⁰, R¹¹, R¹², R¹³and R¹⁵is 5- to 6-membered heteroaryl.

(7-5) The pharmaceutical composition of any of (7-1), (7-2), and (7-4), wherein, in the compound represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—NR₅₁R₅₂;

R¹⁰is carboxy, 3- to 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, or a group —(O(CH₂)_o)_p—OH;

R¹³is 5- or 6-membered heterocycloalkyl; and

o and p are each independently an integer selected from 2 to 4.

(7-6) The pharmaceutical composition of any of (7-1) to (7-5), wherein, in the compound represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from carboxy, 3- to 6-membered heterocycloalkyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

R¹³is 5- or 6-membered heterocycloalkyl; and

o and p are each independently an integer selected from 2 to 4.

(7-7) The pharmaceutical composition of any of (7-1) (7-2), (7-4), and (7-5), wherein, in the compound represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, [HO—((CH₂)_oO)_p]C_1-6alkyl, (C_1-6alkoxy)C_1-8alkyl (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl is optionally substituted with one or more hydroxy groups), C_1-4alkoxyC_1-4alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxyl groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (pyridinyl)C_1-4alkoxy, (pyrimidinyl)C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((C_1-3alkoxy)C_1-4alkyl)amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (carboxy)C_2-6alkynyl, (5- to 6-membered heterocycloalkyl)C_2-6alkynyl (the heterocycloalkyl is optionally substituted with one or more oxo groups), C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is optionally substituted with one or more hydroxy groups), (C_3-6cycloalkyl)C_2-6alkynyl (the cycloalkyl is optionally substituted with one or more hydroxy groups), [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_2-6alkynyl, (C_1-3alkoxy)carbonyl, (morpholino)C_1-4alkylthio (the morpholino is optionally substituted with one or more oxo groups), 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(7-8) The pharmaceutical composition of any of (7-1) (7-2), (7-4), (7-5), and (7-7), wherein, in the compound represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, cyano, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (C_1-6alkoxy)C_1-8alkyl (the alkoxy is substituted with one or more hydroxy groups), C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy (the morpholino moiety may be substituted with one or two substituents selected from oxo and C_1-3alkyl), (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (pyrrolidinyl)C_1-4alkoxy (the pyrrolidinyl moiety is optionally substituted with (C_1-4alkoxy)C_1-3alkyl, C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(oxetanyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is substituted with one or more hydroxy groups), and (C_1-3alkoxy)carbonyl.

(7-9) The pharmaceutical composition of any of (7-1) to (7-8), wherein, in the compound represented by the formula (I), each Ra is independently selected from a halogen atom, hydroxy, cyano, C_1-3alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl (the alkoxy is substituted with one or more hydroxy groups), C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the alkoxy is optionally substituted with one or more hydroxy groups), (carboxy)C_2-6alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl substituted with one or more hydroxy groups, and (C_1-3alkoxy)carbonyl.

(7-10) The pharmaceutical composition of any of (7-1) to (7-9), wherein, in the compound represented by the formula (I), R³is methyl substituted with Re.

(7-11) The pharmaceutical composition of any of (7-1) to (7-10), wherein, in the compound represented by the formula (I), R³is benzyl optionally substituted with one or more substituents Ra on the benzene ring.

(7-12) The pharmaceutical composition of any of (7-1) to (7-11), wherein, in the compound represented by the formula (I), R³is benzyl optionally substituted with one to three substituents Ra on the benzene ring.

(7-13) The pharmaceutical composition of any of (7-1) to (7-6) and (7-10) to (7-12), wherein, in the compound represented by the formula (I), Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom or C_1-3alkoxy;

Rj is a halogen atom, nitro, or cyano; and

Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 5- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkenyl optionally substituted with one or more substituents R¹⁵, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², or C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, or a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵².

(7-14) The pharmaceutical composition of any of (7-13), wherein, in the compound represented by the formula (I), Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy moiety is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², and C_1-4alkylthio optionally substituted with one or more substituents R¹³, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, or a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²;

each R¹⁰is independently carboxy, hydroxy, morpholinyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, or a group —(O(CH₂)_o)_p—OH;

R¹³is morpholinyl; and

o and p are each independently an integer selected from 2 to 4.

(7-15) The pharmaceutical composition of any of (7-1) to (7-6) and (7-10) to (7-13), wherein, in the compound represented by the formula (I), Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom or C_1-3alkoxy;

Rj is a halogen atom, nitro, or cyano; and

(7-16) The pharmaceutical composition of any of (7-14) or (7-15), wherein, in the compound represented by the formula (I), Rk is hydroxy, a halogen atom, (C_1-4alkoxy)carbonyl, 3- to 6-membered heterocycloalkyloxy, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹, C_1-8alkoxy optionally substituted with one or more substituents R¹², or C_1-4alkylthio optionally substituted with one or more substituents R¹³;

each R¹⁰is independently selected from hydroxy, carboxy, morpholinyl, C_1-6alkoxy optionally substituted with one or more hydroxy groups, and a group —(O(CH₂)_o)_p—OH;

each R¹¹is independently selected from hydroxy, carboxy, morpholinyl optionally substituted with one or more oxo groups, C_1-6alkoxy optionally substituted with one or more hydroxy groups, a group —(O(CH₂)_o)_p—OH, and C_3-6cycloalkyl optionally substituted with one or more hydroxy groups;

each R¹²is independently selected from a halogen atom, hydroxy, C_1-6alkoxy optionally substituted with one or more hydroxy groups, (C_1-3alkoxy)carbonyl, 3- to 6-membered heterocycloalkyl, pyridinyl, pyrroryl, and a group —NR³⁹R⁴⁰;

R¹³is morpholinyl; and

o and p are each independently an integer selected from 2 to 4.

(7-17) The pharmaceutical composition of (7-13) or (7-14), wherein, in the compound represented by the formula (I), Rk is a halogen atom, hydroxy, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, [HO—((CH₂)_oO)_p]C_1-6alkyl, (C_1-6alkoxy)C_1-8alkyl (the alkoxy is optionally substituted with one or more hydroxy groups), C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy substituted with one or more hydroxy groups, ((C_1-3alkoxy)carbonyl)C_1-3alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety contains one to three heteroatoms selected from O or N, and is optionally substituted with one or more substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl moiety is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (pyridinyl)C_1-4alkoxy, (pyrimidinyl)C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkoxy(C_1-3alkyl))amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (carboxy)C_2-8alkynyl, (morpholino) C_2-6alkynyl (the morpholino is optionally substituted with one or more oxo groups), C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is optionally substituted with one or more hydroxy groups), (C_3-6cycloalkyl)C_2-6alkynyl (the cycloalkyl is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy)carbonyl, (morpholino)C_1-4alkylthio, 3- to 6-membered oxacycloalkyloxy, or 3- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(7-18) The pharmaceutical composition of (7-13), (7-14), or (7-17), wherein, in the compound represented by the formula (I), Rk is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (morpholino)C_1-4alkyl, (C_1-6alkoxy)C_1-8alkyl (the alkoxy is substituted with one or more hydroxy groups), C_1-6alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-8alkoxy, (pyrrolidinyl)C_1-4alkoxy (the pyrrolidinyl moiety is substituted with (C_1-4alkoxy)C_1-3alkyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(oxetanyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, (carboxy)C_2-8alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is substituted with one or more hydroxy groups), or (C_1-3alkoxy)carbonyl.

(7-19) The pharmaceutical composition of any of (7-13) to (7-18), wherein, in the compound represented by the formula (I), Rk is hydroxy, a halogen atom, C_1-6alkyl, (carboxy)C_1-8alkyl, (C_1-6alkoxy)C_1-8alkyl (the alkoxy is substituted with one or more hydroxy groups), C_1-3alkoxy optionally substituted with one or more halogen atoms, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (morpholino)C_1-6alkoxy, (C_1-6alkoxy)C_1-8alkoxy (the C_1-6alkoxy is substituted with one or more hydroxy groups), (carboxy)C_2-8alkynyl, (morpholino)C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, [HO—((CH₂)_oO)_p]C_2-8alkynyl, (C_1-6alkoxy)C_2-8alkynyl (the alkoxy is substituted with one or more hydroxy groups), or (C_1-3alkoxy)carbonyl.

(7-20) The pharmaceutical composition of any of (7-1) to (7-19), wherein, in the compound represented by the formula (I), R¹, R⁴, and R⁵are as defined in any one of the following (1) to (3):

(1) R¹is a hydrogen atom or C_1-6alkyl;

R⁴is C_1-4alkyl optionally substituted with one or more halogen atom(s), or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl;

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above; and

(3) R¹is a hydrogen atom or linear C_1-6alkyl;

(7-21) The pharmaceutical composition of any of (7-1) to (7-20), wherein, in the compound represented by the formula (I), R¹is C_1-6alkyl;

R⁴is C_1-4alkyl, optionally substituted with one or more halogen atoms, or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl.

(7-22) The pharmaceutical composition of any of (7-1) to (7-20), wherein, in the compound represented by the formula (I), R¹is a hydrogen atom or linear C_1-4alkyl;

(7-23) The pharmaceutical composition of any of (7-1) to (7-20), wherein, in the compound represented by the formula (I), R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is C_1-4alkyl.

(7-24) The pharmaceutical composition of any of (7-1) to (7-4), (7-10) to (7-12) and (7-20), wherein, in the compound represented by the formula (I),

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is C_1-6alkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom, C_2-6alkynyl optionally substituted with one or more substituents R¹¹, C_1-6alkoxy optionally substituted with one or more substituents R¹², 3- to 6-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C_1-4alkoxy-substituted C_1-4alkyl), a

group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, pyrrolyl, a group —NR⁴⁹R⁵⁰, and a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵²;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

(7-25) The pharmaceutical composition of any of (7-1) to (7-7), (7-10) to (7-12), (7-20), and (7-24), wherein, in the compound represented by the formula (I),

each Ra is independently selected from a halogen atom, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (C_1-4alkoxy)C_1-6alkoxy (the C_1-4alkoxy moiety is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-6alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety is optionally substituted with one or two substituents selected from oxo, a halogen atom, C_1-4alkyl (the alkyl is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((C_1-3alkoxy)C_1-4alkyl)amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, C_1-6alkoxy optionally substituted with one or more halogen atoms, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (3- to 6-membered heterocycloalkyl)C_2-6alkynyl (the heterocycloalkyl moiety is optionally substituted with one oxo group), [N—((C_1-3alkoxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_2-6alkynyl, C_2-8alkynyl optionally substituted with one or more hydroxy groups, 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(7-26) The pharmaceutical composition of any of (7-1) to (7-4), (7-10) to (7-13), (7-20) to (7-25), wherein, in the compound represented by the formula (I),

Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom;

Rj is a halogen atom; and

(7-27) The pharmaceutical composition of any of (7-24) to (7-26), wherein, in the compound represented by the formula (I), R¹¹is morpholino;

R¹²is selected from 5- to 6-membered heterocycloalkyl which contains one or two hetero atoms selected from 0 and N, (C_1-4alkoxy)C_1-6alkoxy or a group —NR³⁹R⁴⁰.

(7-28) The pharmaceutical composition of any of (7-13), (7-14) (7-17) or (7-26), wherein, in the compound represented by the formula (I),

Rk is [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, (C_1-4alkoxy)C_1-6alkoxy (the C_1-4alkoxy moiety is optionally substituted with one or more hydroxy groups), (C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy, (carboxy)C_1-6alkoxy, (3- to 6-membered heterocycloalkyl)C_1-6alkoxy (the heterocycloalkyl moiety comprises one to three hetero atom(s) which is selected from O or N and is optionally substituted with one or two substituents selected from oxo, a halogen atom, C_1-4alkyl (wherein the alkyl moiety is optionally substituted with one or more hydroxy groups), (C_1-4alkoxy)C_1-4alkyl (the alkoxy moiety is optionally substituted with one or more hydroxy groups), C_1-4alkoxy, (C_1-4alkoxy)carbonyl, C_1-4alkylthio, morpholino, (C_1-3alkyl)sulfonyl, and (di(C_1-3alkyl)amino)carbonyl), C_1-4alkoxy substituted with a group —NH—CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, [N-(3- to 6-membered oxacycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy, [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, (1,2,4-triazolyl)C_1-4alkoxy, [N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkoxy(C_1-4alkyl))amino]C_1-6alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-6alkoxy, [N—[N—(C_1-4alkyl)carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N—[N—(C_1-4alkyl)carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy, a group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, a group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², C_1-4alkoxy substituted with a group —NH—(CH₂)_w—SO₃H, C_1-4alkoxy substituted with a group —NH—(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, a group —(O(CH₂)_s1)_s2—NR⁴⁵—C(O)R⁴⁶, a group —C(O)NR⁴⁷R⁴⁸, pyridinyl, a group —NR⁴⁹R⁵⁰, a group —(O(CH₂)_y1)_y2—O—CH₂—C(O)NR⁵¹R⁵², (3- to 6-membered heterocycloalkyl)C_2-6alkynyl (the heterocycloalkyl moiety comprises one to three hetero atoms selected from O and N and is optionally substituted with one oxo group), [N—((C_1-3alkoxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_2-6alkynyl, 3- to 6-membered oxacycloalkyloxy, or 4- to 6-membered nitrogen containing heterocycloalkyloxy (the nitrogen containing heterocycloalkyl moiety is optionally substituted with one substituent selected from (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl).

(7-29) The pharmaceutical composition of any of (7-1) to (7-8), (7-10) to (7-12), (7-20) and (7-24), wherein, in the compound represented by the formula (I),

R¹, R⁴, and R⁵are as defined in the following (1) or (2):

(1) R¹is C_1-6alkyl;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl; and

R⁵is a hydrogen atom or C_1-4alkyl; or

(2) R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring; and

R⁴is as defined above;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom, optionally R¹¹-substituted C_2-6alkynyl, and optionally R¹²-substituted C_1-6alkoxy;

R¹¹and R¹²are each independently selected from 5- or 6-membered heterocycloalkyl and —NR³⁹R⁴⁰;

R³⁹and R⁴⁰are each independently selected from hydrogen atom and optionally C_1-6alkoxy-substituted C_1-6alkyl;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

(7-30) The pharmaceutical composition of any of (7-1) to (7-29), wherein, in the compound represented by the formula (I), Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

(7-31) The pharmaceutical composition of any of (7-1) to (7-12), (7-20) to (7-24), (7-29), and (7-30), wherein, in the compound represented by the formula (I), Re is phenyl optionally substituted with one or more substituents Ra;

R¹¹and R¹²are each independently selected from morpholinyl and a group —NR³⁹R⁴⁰;

R⁴is optionally halogen atom-substituted C_1-4alkyl or phenyl;

Ar¹is phenyl, pyridinyl, or pyrimidinyl, wherein the phenyl, pyridinyl, and pyrimidinyl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

(7-32) The pharmaceutical composition of any of (7-1) to (7-4), (7-10) to (7-16), (7-20) to (7-24), (7-26) and (7-29) to (7-31), wherein, in the compound represented by the formula (I), Re is phenyl optionally substituted with one to three substituents Ra;

Ri is a halogen atom;

Rj is a halogen atom; and

Rk is hydroxy, C_2-6alkynyl optionally substituted with a substituent R¹¹, or C_1-6alkoxy optionally substituted with a substituent R¹².

(7-33) The pharmaceutical composition of any of (7-29) to (7-32), wherein, in the compound represented by the formula (I), R¹¹and R¹²are each independently selected from morpholinyl, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino] and [N,N-di(C_1-3alkyl)amino].

(7-34) The pharmaceutical composition of any of (7-29) to (7-33), wherein, in the compound represented by the formula (I), R¹¹and R¹²are each independently selected from morpholinyl, and [N-((methoxy)ethyl)-N-(methyl)amino].

(7-35) The pharmaceutical composition of any of (7-1), (7-3) to (7-6), (7-10) to (7-12), (7-20), (7-23), (7-24), and (7-29), wherein, in the compound represented by the formula (I), R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring;

R⁴is C_1-4alkyl;

R³is C_1-4alkyl substituted with Re;

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

each Ra is independently selected from a halogen atom and C_1-4alkoxy optionally substituted with one or more substituents R¹²;

each R¹²is independently selected from 5- or 6-membered heterocycloalkyl and —NR³⁹R⁴⁰;

R³⁹and R⁴⁰are each independently selected from a hydrogen atom and optionally C_1-4alkoxy-substituted C_1-4alkyl;

Ar¹is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;

each R¹⁴is independently selected from a halogen atom, cyano, C_1-4alkyl optionally substituted with one or more halogen atoms, and C_1-4alkylthio.

(7-36) The pharmaceutical composition of any of (7-1) to (7-35), wherein, in the compound represented by the formula (I), Rb is a halogen atom;

Rc is a halogen atom or C_1-4alkyl optionally substituted with one or more halogen atoms; and

Rd is a halogen atom or 5- or 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

(7-37) The pharmaceutical composition of any of (7-1) to (7-12), (7-20) to (7-25), (7-29) to (7-31), (7-35), and (7-36), wherein, in the compound represented by the formula (I), Ra is selected from a halogen atom, (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, or [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(7-38) The pharmaceutical composition of any of (7-1) to (7-5), (7-10) to (7-16), (7-20) to (7-23), (7-26), (7-29), (7-32), (7-35), and (7-36), wherein, in the compound represented by the formula (I), Re is phenyl optionally substituted with one to three substituents Ra;

Ri and Rj are each independently a halogen atom; and

Rk is C_1-4alkoxy optionally substituted with one or more substituents R¹².

(7-39) The pharmaceutical composition of any of (7-13) to (7-18), (7-20) to (7-23), (7-26) to (7-28), (7-32), (7-33), (7-34), and (7-38) wherein, in the compound represented by the formula (I), Rk is a halogen atom, (morpholino)C_1-4alkoxy, [N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy, [N,N-di(C_1-3alkyl)amino]C_1-4alkoxy.

(7-40) The pharmaceutical composition of any of (7-1) to (7-39), wherein, in the compound represented by the formula (I), Rb is a halogen atom;

Rc is a halogen atom, methyl or trifluoromethyl;

(7-41) The pharmaceutical composition of any of (7-1) to (7-40), wherein, in the compound represented by the formula (I), R¹⁴is each independently selected from methyl, trifluoromethyl, cyano, nitro, a halogen atom, methoxy, ethoxy, trifluoromethoxy, methylthio, methoxycarbonyl and dimethylaminosulfonyl.

(7-42) The pharmaceutical composition of any of (7-1) to (7-41), wherein, in the compound represented by the formula (I), R¹⁴is each independently selected from methyl, trifluoromethyl, cyano, a chlorine atom and methylthio.

(7-43) The pharmaceutical composition of any of (7-1) to (7-42), wherein, in the compound represented by the formula (I), Ar¹is phenyl or 5- to 6-membered heteroaryl which comprises one to three hetero atoms selected from O, S, and N, wherein the phenyl and the heteroaryl is substituted with one to three substituents selected from Rb, Rc, and Rd.

(7-44) The pharmaceutical composition of any of (7-1) to (7-11), (7-20) to (7-25), (7-29) to (7-31), (7-33) to (7-37), and (7-40) to (7-43), wherein, the compound represented by the formula (I) is represented by the formula (I-c);

embedded image

wherein, n1 is an interger selected from 1 to 4, n2 is an interger selected from 0 or more, R¹, R⁴, R⁵, Ar¹, Ra, Rb, Rc, Rd, Re are as defined in any of (7-1) to (7-11), (7-20) to (7-25), (7-29) to (7-31), (7-33) to (7-37), and (7-40) to (7-43).

(7-45) The pharmaceutical composition of (7-44), wherein, in the compound represented by the formula (I-c), n1 is 1 and n2 is 3.

(7-46) The pharmaceutical composition of any of (7-13) to (7-23), (7-26) to (7-28), (7-30), (7-32) to (7-34), (7-36), and (7-38) to (7-43), wherein, the compound represented by the formula (I) is represented by the formula (I-d);

embedded image

wherein n1 is an interger selected from 1 to 4, n3, n4 and n5 is a interger independently selected from 0 or 1, provided that at least one of n3, n4 and n5 is 1, R¹, R⁴, R⁵, Ar¹, Ra, Rb, Rc, Rd, Re, Ri, Rj, and Rk are as defined in any of (7-13) to (7-23), (7-26) to (7-28), (7-30), (7-32) to (7-34), (7-36), and (7-38) to (7-43).

(7-47) The pharmaceutical composition of (7-46), wherein, in the compound represented by the formula (I-d), n1 is 1.

(7-48) The pharmaceutical composition of any of (7-1) to (7-47), wherein, in the compound represented by the formula (I), Ar¹is 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.

(7-49) The pharmaceutical composition of (7-1), which comprises a compound selected from:

(4aR)-1-[(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)—N-[2-(6-cyano-5-methylpyrimidin-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;
(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-ynoic 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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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-morpholin-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-morpholin-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-morpholin-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-pyridazine-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-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-[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-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide;
(2S)-2-[2-[2,3-difluoro-4-[[1-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]butanedioic acid;
3-[2-[2,3-difluoro-4-[[1-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]pentanedioic 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-ene-8-carboxamide;
7-[[2,3-difluoro-4-[2-[methyl(oxetan-3-yl)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;
7-(2,3-difluoro-4-(2-(methyl(oxetan-3-yl)amino)ethoxy)benzyl)-1-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,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;
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;
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]ethanesulfonic acid; and
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]ethanesulfonic acid

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

(7-50) The pharmaceutical composition of any of (7-1) to (7-49) for use in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification.

(7-51) The pharmaceutical composition of any of (7-1) to (7-49) for use in the prevention or treatment of a disease selected from hyperphosphatemia and chronic kidney disease.

(7-52) The pharmaceutical composition of (7-50) or (7-51), wherein the hyperphosphatemia is hyperphosphatemia in a patient with chronic kidney disease.

(7-53) The pharmaceutical composition of (7-50) or (7-51), wherein the chronic kidney disease is at stage 2 to 4 classified by GFR.

(7-54) The pharmaceutical composition of any of (7-1) to (7-49) for use in the prevention or suppression of ectopic calcification.

(7-55) The pharmaceutical composition of any of (7-1) to (7-49) for use in the inhibition of one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2.

(7-56) A pharmaceutical composition comprising a substance that inhibits one or more transporters selected from PiT-1 and PiT-2 and used in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification.

(7-57) A pharmaceutical composition comprising a substance that inhibits one or more transporters selected from PiT-1 and PiT-2 and used in the prevention or suppression of ectopic calcification.

(7-58) The pharmaceutical composition of (7-56) or (7-57), wherein the substance further inhibits NaPi-IIb.

(7-59) The pharmaceutical composition of any of (7-56) to (7-58), wherein the substance inhibits NaPi-IIb, PiT-1, and PiT-2.

(7-60) The pharmaceutical composition of any of (7-56) to (7-59), wherein the substance is a low-molecular compound.

One aspect of the present invention provides the following pharmaceutical compositions (8-1) to (8-24).

(8-1) A pharmaceutical composition comprising a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 and used in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, wherein the substance is administered in combination with a phosphorus adsorbent.

(8-2) A pharmaceutical composition for use in the prevention or suppression of ectopic calcification, comprising a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 wherein the composition is administered in combination with a phosphorus adsorbent.

(8-3) The pharmaceutical composition of (8-1) or (8-2) which is a combined drug comprising the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2, and the phosphorus adsorbent.

(8-4) The pharmaceutical composition of (8-1) or (8-2), wherein the phosphorus adsorbent is administered as separate pharmaceutical compositions.

(8-5) The pharmaceutical composition of any of (8-1), (8-2), and (8-4), wherein the substance that inhibits the one or more transporters and the phosphorus adsorbent are administered simultaneously.

(8-6) The pharmaceutical composition of any of (8-1), (8-2), and (8-4), wherein the substance that inhibits the one or more transporters and the phosphorus adsorbent are administered sequentially.

(8-7) The pharmaceutical composition of any of (8-1), (8-2), (8-4) and (8-6), wherein the substance that inhibits the one or more transporters is administered before or after administration of the phosphorus adsorbent.

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

(8-9) A pharmaceutical composition comprising a phosphorus adsorbent, for use in the prevention or suppression of ectopic calcification, wherein the composition is administered in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2.

(8-10) The pharmaceutical composition of (8-8) or (8-9), wherein the substance that inhibits the one or more transporters is administered simultaneously with the phosphorus adsorbent.

(8-11) The pharmaceutical composition of (8-8) or (8-9), wherein the substance that inhibits the one or more transporters is administered before or after administration of the phosphorus adsorbent.

(8-12) The pharmaceutical composition of any of (8-1) to (8-11), 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.

(8-13) The pharmaceutical composition of any of (8-1) to (8-12), wherein the substance further inhibits NaPi-IIb.

(8-14) A pharmaceutical composition comprising a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 and a phosphorus adsorbent.

(8-15) The pharmaceutical composition of (8-14) for use in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification.

(8-16) The pharmaceutical composition of (8-14) for use in the prevention or suppression of ectopic calcification.

(8-17) The pharmaceutical composition of any of (8-1) to (8-16), 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 of transporters selected from PiT-1 and PiT-2.

(8-18) The pharmaceutical composition of any of (8-1) to (8-16), wherein the substance further inhibits NaPi-IIb.

(8-19) The pharmaceutical composition of any of (8-1) to (8-18), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 is a compound of any of (7-1) to (7-49) or a salt thereof or a solvate of the compound or the salt.

(8-20) The pharmaceutical composition of any of (8-1) or (8-19), wherein the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 is a compound represented by any one of the following formulae (1) to (5):

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(wherein Ac is an acetyl group)

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

(8-21) The pharmaceutical composition of any of (8-1) or (8-20), 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):

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

(8-22) The pharmaceutical composition of any of (8-1) to (8-21), wherein the phosphorus adsorbent is a nonmetallic polymer adsorbent, a calcium salt preparation, or a metallic salt preparation.

(8-23) The pharmaceutical composition of any of (8-1) to (8-22), wherein the phosphorus adsorbent is any one of medicaments selected from bixalomer, sevelamer carbonate, sevelamer hydrochloride, precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, calcium salt of keto-acid, lanthanum carbonate, aluminum hydroxide, sucroferric oxyhydroxide, Fermagate, and ferric citrate hydrate.

(8-24) The pharmaceutical composition of any of (8-1) to (8-23), wherein the phosphorus adsorbent is sevelamer carbonate.

One aspect of the present invention provides the following methods (9-1) to (9-6):

(9-1) A method for preventing or treating a disease selected from 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 a phosphorus adsorbent.

(9-2) A method for preventing or suppressing 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 adsorbent.

(9-3) The method of (9-1) or (9-2), wherein the substance that inhibits the one or more transporters and the phosphorus adsorbent are administered as a combined drug.

(9-4) The method of (9-1) or (9-2), wherein the substance that inhibits the one or more transporters and the phosphorus adsorbent are administered as separate pharmaceutical compositions.

(9-5) The method of any of (9-1), (9-2) and (9-4), wherein the the substance that inhibits the one or more transporters and the phosphorus adsorbent are administered simultaneously.

(9-6) The method of any of (9-1), (9-2) and (9-4), wherein the substance that inhibits the one or more transporters is administered before or after administration of the phosphorus adsorbent.

One aspect of the present invention provides the following uses (10-1) to (10-10).

(10-1) A use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 in combination with a phosphorus adsorbent, for preventing or treating a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification.

(10-2) A use of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 in combination with a phosphorus adsorbent, for preventing or suppressing ectopic calcification.

(10-3) The use of (10-1) or (10-2), wherein the substance that inhibits the one or more transporters are administered to a subject as a pharmaceutical composition separately from the phosphorus adsorbent.

(10-4) The use of any of (10-1) or (10-3), wherein the substance that inhibits the one or more transporters are administered to the subject simultaneously with the phosphorus adsorbent.

(10-5) The use of any of (10-1) or (10-3), wherein the substance that inhibits the one or more transporters are administered to the subject before or after administration of the phosphorus adsorbent.

(10-6) A use of a phosphorus adsorbent administered in combination with a substance that inhibits 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 hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification.

(10-7) A use of a phosphorus adsorbent administered in combination with a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2, for use in the prevention or suppression of ectopic calcification.

(10-8) The use of (10-6) or (10-7), wherein the substance that inhibits the one or more transporters are administered to a subject as a pharmaceutical composition different from the phosphorus adsorbent.

(10-9) The use of any of (10-6) or (10-8), wherein the phosphorus adsorbent is administered to the subject simultaneously with the substance that inhibits the one or more transporters.

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

ADVANTAGIOUS EFFECTS OF INVENTION

The compound, the salt thereof or the solvate of the compound or the salt has an excellent NaPi-IIb inhibitory effect, PiT-1 inhibitory effect, or PiT-2 inhibitory effect, and is useful as a prevention and/or treatment agent for hyperphosphatemia. Further, the compound, the salt thereof or the solvate of the compound or the salt is useful as a prevention and/or treatment agent for secondary hyperparathyroidism, or chronic renal failure. Further, the pharmaceutical composition of the present invention is useful as a prevention and/or treatment agent for a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and vascular calcification.

DESCRIPTION OF EMBODIMENTS

Hereinafter, a compound of the present invention or a salt thereof, or a solvate of the compound or the salt, a method for producing the same, and a pharmaceutical drug and a pharmaceutical composition each containing this compound will be described.

Definition

In the present invention, a “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, etc. include a fluorine atom, a chlorine atom, and a 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, alkenyl, alkylthio, etc.) include a fluorine atom. Specific examples of groups having the halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.

In the present invention, “C_1-3alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 3 carbon atoms by the loss of one arbitrary hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, and isopropyl.

In the present invention, “C_1-4alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 4 carbon atoms by the loss of one arbitrary 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_1-5alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 5 carbon atoms by the loss of one arbitrary hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, and 1-ethylpropyl.

In the present invention, “C_1-6alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms by the loss of one arbitrary hydrogen atom. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 4-methylpentyl, and 2-ethylbutyl.

In the present invention, “C_1-8alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 8 carbon atoms by the loss of one arbitrary hydrogen atom. Specific examples thereof include the groups listed above in the definition of “C_1-6alkyl” 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_1-10alkyl” refers to a monovalent group derived from a linear and branched saturated aliphatic hydrocarbon having 1 to 10 carbon atoms by the loss of one arbitrary hydrogen atom. Specific examples thereof include the groups listed above in the definition of “C_1-8alkyl” 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_1-6alkyl” refers to a monovalent group derived from a linear saturated aliphatic hydrocarbon having 1 to 6 carbon atoms by the loss of one arbitrary hydrogen atom. “Linear C_1-6alkyl” specifically means methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.

In the present invention, “linear C_1-10alkyl” refers to a monovalent group derived from a linear saturated aliphatic hydrocarbon having 1 to 10 carbon atoms by the loss of one arbitrary hydrogen atom. “Linear C_1-10alkyl” specifically means methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

In the present invention, “morpholino” means morpholin-4-yl.

In the present invention, “(morpholino)C_1-6alkyl” means a C_1-6alkyl group substituted with morpholino. “C_1-6alkyl” is as defined above. Specific examples thereof include morpholinomethyl, morpholinoethyl, morpholino-n-propyl, morpholinoisopropyl, morpholino-n-butyl, morpholinoisobutyl, morpholino-sec-butyl, morpholino-t-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_1-4alkyl” means a C_1-4alkyl group substituted with morpholino. “C_1-4alkyl” is as defined above. Specific examples thereof include morpholinomethyl, morpholinoethyl, morpholino-n-propyl, morpholinoisopropyl, morpholino-n-butyl, morpholinoisobutyl, morpholino-sec-butyl, morpholino-t-butyl, and morpholino-1-methylpropyl. Preferred examples thereof include morpholinomethyl.

In the present invention, “(oxetanyl)C_1-4alkyl” means a C_1-4alkyl group substituted with oxetanyl. “C_1-4alkyl” is as defined above. Specific examples thereof include oxetanylmethyl, oxetanylethyl, oxetanyl-n-propyl, oxetanylisopropyl, oxetanyl-n-butyl, oxetanylisobutyl, oxetanyl-sec-butyl, oxetanyl-t-butyl, and oxetanyl-1-methylpropyl. Preferred examples thereof include oxetanylmethyl.

In the present invention, “(4- to 6-membered heterocycloalkyl)C_1-4alkyl” means C_1-4alkyl substituted with 4- to 6-membered heterocycloalkyl. “C_1-4alkyl” is as defined above. “4- to 6-membered heterocycloalkyl” means a saturated heterocyclic group composed of 4 to 6 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. “(4- to 6-membered heterocycloalkyl)C_1-4alkyl” includes “(morpholino)C_1-4alkyl” and “(oxetanyl)C_1-4alkyl”.

In the present invention, “(carboxy)C_1-8alkyl” means C_1-8alkyl substituted with carboxy. “C_1-8alkyl” 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_1-6alkoxy)C_1-8alkyl” means C_1-8alkyl substituted with C_1-6alkoxy. “C_1-6alkoxy” and “C_1-8alkyl” 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_1-3alkoxy)C_1-4alkyl” means C_1-4alkyl substituted with C_1-3alkoxy. “C_1-3alkoxy” and “C_1-4alkyl” 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_1-4alkoxy)C_1-4alkyl” means C_1-4alkyl substituted with C_1-4alkoxy. “C_1-4alkoxy” and “C_1-4alkyl” are as defined above and below. Specific examples thereof include the groups listed above in the definition of “(C_1-3alkoxy)C_1-4alkyl” as well as n-butoxymethyl, n-butoxyethyl, n-butoxy-n-propyl, and n-butoxy-n-butyl.

In the present invention, “(C_1-3alkoxy)C_1-6alkyl” means C_1-6alkyl substituted with C_1-3alkoxy. “C_1-3alkoxy” and “C_1-6alkyl” are as defined above and below. Specific examples thereof include the groups listed above in the definitions of “(C_1-3alkoxy)C_1-4alkyl” and “(C_1-4alkoxy)C_1-4alkyl”. Preferred examples thereof include methoxy-n-propyl.

In the present invention, “[HO—((CH₂)_oO)_p]C_1-6alkyl” refers to C_1-6alkyl substituted with a group —(O(CH₂)_o)_p—OH. C_1-6alkyl is as defined above. Specific examples thereof include [HO—((CH₂)₂O)₃]propyl.

In the present invention, “C_1-5alkylene” refers to a divalent group derived from a linear or branched saturated aliphatic hydrocarbon having 1 to 5 carbon atoms by the loss of two arbitrary hydrogen atoms. “C_1-5alkylene” includes “C_1-3alkylene”. Specific examples thereof include —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH(CH₂CH₃)—, —C(CH₂CH₃)₂—, and —CH(CH₂CH₂CH₃)—. —CH₂— is preferred.

In the present invention, two or more substituents R²on a 5- to 8-membered saturated heterocyclic ring may together form C_1-5alkylene that links the ring atoms to which they are attached. In this case, the saturated heterocyclic ring forms a bicyclo ring or tricycle ring and so on.

In the present invention, “C_2-10alkynyl” refers to a monovalent group derived from a linear or branched aliphatic hydrocarbon having 2 to 10 carbon atoms and having at least one triple bond (two adjacent SP carbon atoms) by the loss of 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, heptadiynyl, octynyl, and octadiynyl.

In the present invention, “optionally substituted C_2-10alkynyl” means unsubstituted C_2-10alkynyl described above or C_2-10alkynyl on which one or more hydrogen atoms are replaced with predetermined substituent(s). Two or more substituents on this group may be the same as or different from each other. One carbon atom may be substituted with a plurality of substituents.

In the present invention, “C_2-6alkynyl” refers to a monovalent group derived from a linear or branched aliphatic hydrocarbon having 2 to 6 carbon atoms and having at least one triple bond (two adjacent SP carbon atoms) by the loss of 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_2-6alkynyl” means unsubstituted C_2-6alkynyl described above or C_2-6alkynyl on which one or more hydrogen atoms are replaced with predetermined substituent(s). Two or more substituents on this group may be the same as or different from each other. One carbon atom may be substituted with a plurality of substituents.

In the present invention, “(carboxy)C_2-6alkynyl” means C_2-6alkynyl substituted with carboxy. C_2-6alkynyl 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_1-6alkoxy)C_2-8alkynyl” means C_2-8alkynyl substituted with C_1-6alkoxy. C_1-6alkoxy and C_2-8alkynyl 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_2-6alkynyl” means C_2-6alkynyl substituted with morpholino. C_2-6alkynyl 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_2-6alkynyl substituted with oxo group(s)” include (morpholino)C_2-6alkynyl substituted with one or two oxo groups. Preferred examples thereof include 3-(3-oxomorpholin-4-yl)-1-propynyl and (1,1-dioxothiomorpholin-4-yl)-1-propynyl.

In the present invention, “(3- to 6-membered oxacycloalkyl)C_2-6alkynyl” means C_2-6alkynyl substituted with 3- to 6-membered oxacycloalkyl. 3- to 6-Membered oxacycloalkyl and C_2-6alkynyl are as defined in the specification.

In the present invention, “(oxetanyl)C_2-6alkynyl” means C_2-6alkynyl substituted with oxetanyl. C_2-6alkynyl 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_2-6alkynyl” means C_2-6alkynyl substituted with pyrrolidino. C_2-6alkynyl 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_3-6cycloalkyl)C_2-6alkynyl” means C_2-6alkynyl substituted with C_3-6cycloalkyl. C_3-6cycloalkyl and C_2-6alkynyl 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—((CH₂)_oO)_p]C_2-8alkynyl” means C_2-8alkynyl substituted with a group —(O(CH₂)_o)_p—OH. C_2-8alkynyl is as defined above. Specific examples thereof include [HO—((CH₂)₂O)₃]propynyl and [HO—((CH₂)₂O)₂]propynyl.

In the present invention, “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_2-6alkynyl” means C_2-6alkynyl substituted with N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino. In this context, “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]” and “C_2-6alkynyl” are as defined in this specification. 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_1-3alkoxy” means a C_1-3alkyl-O— group. In this context, C_1-3alkyl is as defined above. Specific examples thereof include methoxy, ethoxy, 1-propoxy, and 2-propoxy.

In the present invention, “C_1-4alkoxy” means a C_1-4alkyl-O— group. In this context, C_1-4alkyl is as defined above. Specific examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy.

In the present invention, “C_1-5alkoxy” means a C_1-5alkyl-O— group. In this context, C_1-5alkyl is as defined above. Specific examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, and 1-pentyloxy.

In the present invention, “C_1-6alkoxy” means a C_1-6alkyl-O— group. In this context, C_1-6alkyl is as defined above. Specific examples thereof include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, and 1-hexyloxy.

In the present invention, “C_1-8alkoxy” means a C_1-8alkyl-O— group. Specific examples thereof include the groups listed above in the definition of “C_1-6alkoxy” as well as 1-heptyloxy and 1-octyloxy.

In the present invention, “(carboxy)C_1-8alkoxy” means C_1-6alkoxy substituted with one carboxy group. “C_1-8alkoxy” is as defined above. Specific examples thereof include carboxy-n-propoxy, carboxy-n-butoxy, carboxy-n-pentoxy, and carboxy-n-hexoxy.

In the present invention, “(morpholino)C_1-6alkoxy” means C_1-6alkoxy substituted with morpholino. “C_1-6alkoxy” is as defined above. Specific examples thereof include morpholinomethoxy, morpholinoethoxy, morpholino-1-propoxy, morpholino-2-propoxy, morpholino-n-butoxy, morpholino-1-butoxy, morpholino-sec-butoxy, morpholino-t-butoxy, morpholino-1-pentyloxy, and morpholino-1-hexyloxy. Preferred examples thereof include morpholinoethoxy.

In the present invention, “(3- to 6-membered oxacycloalkyl)C_1-4alkoxy” means C_1-4alkoxy substituted with 3- to 6-membered oxacycloalkyl. “C_1-4alkoxy” is as defined above. 3- to 6-membered oxacycloalkyl means a saturated heterocyclic group composed of 3 to 6 ring-constituting atoms containing one or two, (preferably one) oxygen atom. “(3- to 6-membered oxacycloalkyl)C_1-4alkoxy” includes (oxiranyl)C_1-4alkoxy, (oxetanyl)C_1-4alkoxy, and (oxolanyl)C_1-4alkoxy. Specific examples thereof include oxiranylmethoxy, oxiranylethoxy, oxiranyl-1-propoxy, oxiranyl-n-butoxy, oxetanylmethoxy, oxetanylethoxy, oxetanyl-1-propoxy, oxetanyl-n-butoxy, oxolanylmethoxy, oxolanylethoxy, oxolanyl-1-propoxy, and oxolanyl-n-butoxy. Preferred examples thereof include oxolanylmethoxy, oxiranylmethoxy, and oxetanylmethoxy.

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

In the present invention, “4- to 6-membered nitrogen containing heterocycloalkyloxy” means 4- to 6-membered nitrogen containing heterocycloalkyl-O—. “4- to 6-membered nitrogen containing heterocycloalkyl” means a saturated heterocyclic group composed of 4 to 6 ring-constituting atoms containing one or two nitrogen atoms. Specific examples thereof include pyrrolidinyloxy and azetidinyloxy.

In the present invention, “(pyridinyl)C_1-4alkoxy” means C_1-4alkoxy substituted with pyridinyl. “C_1-4alkoxy” is as defined above. Specific examples thereof include pyridinylmethoxy, pyridinylethoxy, pyridinyl-1-propoxy, and pyridinyl-n-butoxy. Preferred examples thereof include pyridinylmethoxy.

In the present invention, “(pyrimidinyl)C_1-4alkoxy” means C_1-4alkoxy substituted with pyrimidinyl. “C_1-4alkoxy” is as defined above. Specific examples thereof include pyrimidinylmethoxy, pyrimidinylethoxy, pyrimidinyl-1-propoxy, and pyrimidinyl-n-butoxy. Preferred examples thereof include pyrimidinylmethoxy.

In the present invention, “(1,2,4-triazolyl)C_1-4alkoxy” means C_1-4alkoxy substituted with 1,2,4-triazolyl. “C_1-4alkoxy” is as defined above. Specific examples thereof include 1,2,4-triazolylmethoxy, 1,2,4-triazolylethoxy, 1,2,4-triazolyl-1-propoxy, and 1,2,4-triazolyl-n-butoxy. Preferred examples thereof include 1,2,4-triazolylethoxy.

In the present invention, “(3- to 6-membered heterocycloalkyl)C_1-6alkoxy” means C_1-6alkoxy substituted with 3- to 6-membered heterocycloalkyl. 3- to 6-membered heterocycloalkyl means a saturated heterocyclic group composed of 3 to 6 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. C_1-6alkoxy is as defined above. “(3- to 6-membered heterocycloalkyl)C_1-6alkoxy” includes (morpholino)C_1-6alkoxy, (3- to 6-membered oxacycloalkyl)C_1-4alkoxy, (pyrrolidinyl)C_1-4alkoxy, (azetidinyl)C_1-4alkoxy, and (piperidinyl)C_1-4alkoxy. Specific examples thereof include morpholinomethoxy, morpholinoethoxy, morpholino-1,1-dimethyl-ethoxy(morpholino-t-butoxy), morpholino-1-methyl-ethoxy(morpholino-2-propoxy), tetrahydrofuranylmethoxy, pyrrolidinylmethoxy, pyrrolidinylethoxy, azetidinylmethoxy, azetidinylethoxy, piperidinylmethoxy, piperidinylethoxy, piperazinylmethoxy, piperazinylethoxy.

In the present invention, “(5- or 6-membered heteroaryl)C_1-4alkoxy” means C_1-4alkoxy substituted with 5- or 6-membered heteroaryl. 5- or 6-membered heteroaryl and C_1-4alkoxy are as defined herein. Specific examples thereof include 1,2,4-triazolylethoxy.

In the present invention, “(C_1-6alkoxy)C_1-6alkoxy” means C_1-6alkoxy substituted with C_1-6alkoxy. “C_1-6alkoxy” is as defined above. “(C_1-6alkoxy)C_1-6alkoxy” includes “(C_1-4alkoxy)C_1-6alkoxy”, “C_1-3alkoxy(C_1-4alkoxy)”, and the like. Specific examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxymethoxy, propoxyethoxy, propoxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy, butoxymethoxy, butoxyethoxy, butoxypropoxy, butoxybutoxy, methoxypentoxy, ethoxypentoxy, propoxypentoxy, butoxypentoxy, pentoxymethoxy, pentoxyethoxy, pentoxypropoxy, pentoxybutoxy, pentoxypentoxy, methoxyhexoxy, ethoxyhexoxy, propoxyhexoxy, butoxyhexoxy, pentoxyhexoxy, hexoxymethoxy, hexoxyethoxy, hexoxypropoxy, hexoxybutoxy, hexoxypentoxy, and hexoxyhexoxy. Preferred examples thereof include propoxybutoxy, propoxypentoxy, and propoxyhexoxy.

In the present invention, “(C_1-6alkoxy)C_1-8alkoxy” means C_1-8alkoxy substituted with C_1-6alkoxy. “C_1-6alkoxy” and “C_1-8alkoxy” are as defined above. Specific examples thereof include the groups listed above in the definition of “(C_1-6alkoxy)C_1-6alkoxy” as well as hexoxyheptyloxy and hexoxyoctyloxy.

In the present invention, “(C_1-3alkoxy(C_1-4alkoxy))C_1-4alkoxy” means C_1-4alkoxy substituted with C_1-3alkoxy(C_1-4alkoxy). “C_1-3alkoxy(C_1-4alkoxy)” means C_1-4alkoxy substituted with C_1-3alkoxy. “C_1-4alkoxy” and “C_1-3alkoxy” are as defined above. Specific examples thereof include methoxyethoxyethoxy, ethoxyethoxyethoxy, and methoxyethoxymethoxy.

In the present invention, “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino. In this context, “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]” means amino substituted with (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl. (C_1-3alkoxy)C_1-4alkyl and C_1-3alkyl are as defined above. Specific examples of “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy” include [Nmethoxyethyl)-N-(methyl)amino]ethoxy, [N-(methoxy-1,1-dimethylethyl)-N-(methyl)amino]ethoxy, and [N-(-methoxy-2-methyl-1-propyl)-N-(methyl)amino]ethoxy.

In the present invention, “[N-(3- to 6-membered heterocycloalkyl)-N—(C_1-3alkyl)amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N-(3- to 6-membered heterocycloalkyl)-N—(C_1-3alkyl)amino. In this context, “[N-(3- to 6-membered heterocycloalkyl)-N—(C_1-3alkyl)amino]” means amino substituted with 3- to 6-membered heterocycloalkyl and C_1-3alkyl. 3- to 6-membered heterocycloalkyl is as defined herein. Specific examples thereof include [N-tetrahydrofuranyl-N-(methyl)amino]ethoxy, [N-tetrahydropyranyl-N-(methyl)amino]ethoxy, and [N-oxetanyl-N-(methyl)amino]ethoxy.

In the present invention, [N,N-di((hydroxy)C_1-4alkyl)-amino]C_1-4alkoxy means C_1-4alkoxy substituted with N,N-di((hydroxy)C_1-4alkyl)-amino. “[N,N-di((hydroxy)C_1-4alkyl)-amino]” means amino substituted with two (hydroxy)C_1-4alkyl groups. (Hydroxy)C_1-4alkyl means C_1-4alkyl substituted with one hydroxy group. Specific examples thereof include [N,N-di(2-hydroxyethyl)amino]ethoxy.

In the present invention, “[N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino. [N—((C_1-3alkoxy)carbonyl)C_1-3alkyl-N—(C_1-3alkyl)amino] means amino substituted with ((C_1-3alkoxy)carbonyl)C_1-3alkyl and C_1-3alkyl. “((C_1-3alkoxy)carbonyl)C_1-3alkyl” means C_1-3alkyl substituted with (C_1-3alkoxy)carbonyl. Specific examples thereof include [N-((methoxy)carbonyl)methyl-N-methylamino]ethoxy.

In the present invention, “[N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino. “N-(hydroxy)C_1-4alkyl-N—(C_1-3alkyl)amino” means amino substituted with (hydroxy)C_1-4alkyl and C_1-3alkyl. “(Hydroxy)C_1-4alkyl” means C_1-4alkyl substituted with one hydroxy group. Specific examples thereof include [N-(2-hydroxyethyl)-N-methylamino]ethoxy.

In the present invention, “[N,N-di((C_1-3alkoxy)C_1-4alkyl)amino]C_1-6alkoxy” means C_1-6alkoxy substituted with N,N-di((C_1-3alkoxy)C_1-4alkyl)amino. “N,N-di((C_1-3alkoxy)C_1-4alkyl)amino” means amino substituted with two (C_1-3alkoxy)C_1-4alkyl groups. “(C_1-3alkoxy)C_1-4alkyl” is as defined above. Specific examples thereof include [N,N-di((methoxy)ethoxy)amino]ethoxy.

In the present invention, “[N,N-di(C_1-3alkyl)amino]C_1-6alkoxy” means C_1-6alkoxy substituted with N,N-di(C_1-3alkyl)amino. “N,N-di(C_1-3alkyl)amino” means amino substituted with two C_1-3alkyl groups. “C_1-6alkoxy” and “C_1-3alkyl” are as defined above. Specific examples thereof include 3-[N,N-di(methyl)amino]-2,2-dimethyl-propoxy.

In the present invention, “[N—[N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N—[N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl)amino. C_1-4alkoxy is as defined before. “N—[N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl)amino]C_1-4alkyl-N—(C_1-3alkyl) amino” means amino substituted with [N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl) amino]C_1-4alkyl and C_1-3alkyl. C_1-3alkyl is as defined before. “[N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl) amino]C_1-4alkyl” means C_1-4alkyl substituted with N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl) amino. “N—(C_1-4alkyl) carbonyl-N—(C_1-3alkyl) amino” means amino substituted with (C_1-4alkyl) carbonyl and C_1-3alkyl. Specific examples thereof include 2-[N-[2-(N-acetyl-N-(methyl) amino)ethyl]-N-(methyl) amino]ethoxy.

In the present invention, “[N—[N—(C_1-4alkyl) carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl) amino]C_1-4alkoxy” means C_1-4alkoxy substituted with N—[N—(C_1-4alkyl) carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl) amino. C_1-4alkoxy is as defined before. “N—[N—(C_1-4alkyl) carbonyl-amino]C_1-4alkyl-N—(C_1-3alkyl) amino” means amino substituted with [N—(C_1-4alkyl) carbonyl-amino]C_1-4alkyl and C_1-3alkyl. C_1-3alkyl is as defined before. “[N—(C_1-4alkyl) carbonyl-amino]C_1-4alkyl” means C_1-4alkyl substituted with a N—(C_1-4alkyl) carbonyl-amino. “N—(C_1-4alkyl) carbonyl-amino” means amino substituted with a (C_1-4alkyl) carbonyl. Specific examples thereof include 2-[N-[2-(acetylamino)ethyl]-N-(methyl) amino]ethoxy.

In the present invention, “C_1-3alkylthio” means a C_1-3alkyl-S— group. In this context, C_1-3alkyl is as defined above. Specific examples thereof include methylthio, ethylthio, n-propylthio, and i-propylthio.

In the present invention, “C_1-4alkylthio” means a C_1-4alkyl-S— group. In this context, C_1-4alkyl is as defined above. Specific examples thereof include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, and t-butylthio.

In the present invention, “(morpholino)C_1-4alkylthio” means C_1-4alkylthio substituted with morpholino. C_1-4alkylthio is as defined above. Specific examples thereof include morpholinomethylthio, morpholinoethylthio, morpholino-n-propylthio, morpholino-1-propylthio, morpholino-n-butylthio, morpholino-1-butylthio, and morpholino-t-butylthio. Preferred examples thereof include morpholinoethylthio.

In the present invention, “(5- or 6-membered heterocycloalkyl)C_1-4alkylthio” means C_1-4alkylthio substituted with 5- or 6-membered heterocycloalkyl. 5- or 6-membered heterocycloalkyl and C_1-4alkylthio are as defined herein. “(5- or 6-membered heterocycloalkyl)C_1-4alkylthio” includes “(morpholino)C_1-4alkylthio”. Preferred examples thereof include 2-morpholinoethylthio.

In the present invention, “(C_1-6alkyl)carbonyl” means a C_1-6alkyl-C(O)— group. In this context, C_1-6alkyl is as defined above. “(C_1-6alkyl)carbonyl” includes “(C_1-4alkyl)carbonyl”. Specific examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-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_1-3alkyl)amino)carbonyl” means carbonyl substituted with di(C_1-3alkyl)amino. “Di(C_1-3alkyl)amino” means amino substituted with two C_1-3alkyl groups. Specific examples thereof include dimethylaminocarbonyl and diethylaminocarbonyl.

In the present invention, “(C_1-3alkyl)sulfonyl” means a C_1-3alkyl-SO₂— group. In this context, C_1-3alkyl is as defined above. Specific examples thereof include methylsulfonyl, ethylsulfonyl, and n-propylsulfonyl. Preferred examples thereof include methylsulfonyl.

In the present invention, “(C_1-6alkoxy)carbonyl” means a C_1-6alkyl-O—C(O)— group. In this context, C_1-6alkyl is as defined above. Specific examples thereof include groups listed later in the definition of “(C_1-4alkoxy)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_1-4alkoxy)carbonyl” means a C_1-4alkyl-O—C(O)— group. In this context, C_1-4alkyl is as defined above. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, and 1-methylpropoxycarbonyl.

In the present invention, “(C_1-3alkoxy)carbonyl” means a C_1-3alkyl-O—C(O)— group. In this context, C_1-3alkyl is as defined above. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and i-propoxycarbonyl.

In the present invention, “((C_1-4alkoxy)carbonyl)C_1-6alkyl” means C_1-6alkyl substituted with (C_1-4alkoxy)carbonyl. In this context, (C_1-4alkoxy)carbonyl and C_1-6alkyl are as defined above. Specific examples thereof include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, n-propoxycarbonylmethyl, and i-propoxycarbonylmethyl. Preferred examples thereof include methoxycarbonylmethyl and methoxycarbonylethyl.

In the present invention, “((C_1-3alkoxy)carbonyl)C_1-3alkoxy” means C_1-3alkoxy substituted with a (C_1-3alkoxy)carbonyl group. In this context, (C_1-3alkoxy)carbonyl and C_1-3alkyl are as defined above. Specific examples thereof include methoxycarbonylmethoxy, methoxycarbonylethoxy, ethoxycarbonylmethoxy, ethoxycarbonylethoxy, n-propoxycarbonylmethoxy, and i-propoxycarbonylmethoxy. Preferred examples thereof include methoxycarbonylmethoxy and methoxycarbonylethoxy.

In the present invention, “C_6-10aryl” means a monovalent aromatic hydrocarbon ring group. Examples of C_6-10aryl include phenyl, 1-naphthyl, and 2-naphthyl.

In the present invention, “(C_6-10aryl)carbonyl” means a C_6-10aryl-C(O)— group. In this context, C_6-10aryl is as defined above. Specific examples thereof include phenylcarbonyl, 1-naphthylcarbonyl, and 2-naphthylcarbonyl.

In the present invention, “5- to 10-membered heteroaryl” means an aromatic ring group composed of 5 to 10 ring-constituting atoms containing one or several (e.g., 1 to 5, preferably 1 to 3) heteroatoms. The ring may be a monocyclic or bicyclic ring. Examples of “5- to 10-membered heteroaryl” include “5- or 6-membered heteroaryl”. Specific examples of “5- to 10-membered heteroaryl” include thienyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, quinolinyl, isoquinolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, indolyl, imidazolyl, furyl, thioxazolyl, pyrrolyl, tetrazolyl, oxopyrimidinyl, naphthyl, benzodioxinyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzothienyl, benzofuranyl, benzopyranyl, and triazolyl.

In the present invention, “5- or 6-membered heteroaryl” means an aromatic ring group composed of 5 or 6 ring-constituting atoms containing one or several (e.g., 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, a “C_3-6saturated carbocyclic ring” refers to a cycloalkane ring having 3 to 6 ring-constituting carbon atoms and includes, for example, cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In the formula (I), R¹and R⁵together with the carbon atom to which they are attached may form a C_3-6saturated carbocyclic ring. In this case, the C_3-6saturated carbocyclic ring forms a spiro ring. In the formula (I), the C_3-6saturated carbocyclic ring formed by R¹and R⁵together with the carbon atom to which they are attached is preferably cyclobutane, cyclopentane, or cyclohexane, particularly preferably cyclobutane or cyclopentane.

In the present invention, a “5- to 8-membered saturated heterocyclic ring” means a saturated heterocyclic group composed of 5 to 8 ring-constituting atoms containing one N as a heteroatom. Specific examples thereof include pyrrolidine, piperidine, azepane, and azocane and particularly include pyrrolidine and piperidine.

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

When Re (or Rx) is C_6-10aryl optionally substituted with one or more substituents Ra (or Ry) or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra (or Ry), the C_6-10aryl is preferably phenyl, and the 5- to 10-membered heteroaryl is preferably indolyl. Particularly, when R⁴and R⁵together with the carbon atom and nitrogen atom to which they are attached do not form a 5- to 8-membered saturated heterocyclic ring, Re is preferably phenyl.

In the present invention, Ar¹(or Ar¹⁰¹) is preferably phenyl, naphthyl, furyl, thienyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, quinolinyl, isoquinolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, pyridinyl, pyrimidinyl, or indolyl. These groups are each optionally substituted with one to three substituents selected from Rb (or Rz¹), Rc (or Rz²), and Rd (or Rz³). When R⁴and R⁵together with the carbon atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring or in the case of the compound represented by the formula (II), Ar¹(or Ar¹⁰¹) is more preferably phenyl, furyl, pyridinyl, or pyrimidinyl.

When R⁴and R⁵together with the carbon atom and nitrogen atom to which they are attached do not form a 5- to 8-membered saturated heterocyclic ring, Ar¹is preferably phenyl, pyridinyl, or pyrimidinyl.

In the present invention, Rd (or Rz³) is preferably phenyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, furyl, thiadiazolyl, thioxazolyl, oxadiazolyl, pyrrolyl, tetrazolyl, oxopyrimidinyl, naphthyl, benzodioxinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indazolyl, benzothienyl, benzofuranyl, benzopyranyl, piperazinyl, piperidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, dioxopyrrolidinyl, dioxopiperidinyl, dioxotetrahydropyrimidinyl, oxoimidazolidinyl, or dioxoimidazolidinyl. These groups are each optionally substituted with one or more substituents R¹⁴. When R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring or in the case of the compound represented by the formula (II), Rd (or Rz³) is preferably phenyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, more preferably phenyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, or piperidinyl. When R⁴and R⁵together with the carbon atom and the nitrogen atom to which they are attached do not form a 5- to 8-membered saturated heterocyclic ring, Rd (or Rz³) is preferably phenyl, pyridinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl, more preferably phenyl, pyridinyl, or pyrimidinyl.

In the present invention, “C_3-6cycloalkyl” means a cyclic saturated aliphatic hydrocarbon group having 3 to 6 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In the present invention, “C_3-7cycloalkyl” means a cyclic saturated aliphatic hydrocarbon group having 3 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 composed of 3 to 10 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic heterocycloalkyl. Specific examples of “3- to 10-membered heterocycloalkyl” include groups listed later in the definition of “4- to 10-membered heterocycloalkyl” as well as oxiranyl.

In the present invention, “4- to 10-membered heterocycloalkyl” means a saturated heterocyclic group composed of 4 to 10 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic 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- to 10-membered heterocycloalkyl” include groups listed later in the definition of “5- to 10-membered heterocycloalkyl” as well as oxetanyl, azetidinyl, and 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl.

In the present invention, “5- to 10-membered heterocycloalkyl” means a saturated heterocyclic group composed of 5 to 10 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic heterocycloalkyl. Examples of “5- to 10-membered heterocycloalkyl” include “6- to 8-membered heterocycloalkyl” and “5- or 6-membered heterocycloalkyl”. Specific examples of “5- to 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- to 8-membered heterocycloalkyl” means a saturated heterocyclic group composed of 4 to 8 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic heterocycloalkyl. Specific examples of “4- to 8-membered heterocycloalkyl” include those described as specific examples of “5- to 8-membered heterocycloalkyl”.

In the present invention, “5- to 8-membered heterocycloalkyl” means a saturated heterocyclic group composed of 5 to 8 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic heterocycloalkyl. Examples of “5- to 8-membered heterocycloalkyl” include “6- to 8-membered heterocycloalkyl” and “5- or 6-membered heterocycloalkyl”. Specific examples of “5- to 8-membered heterocycloalkyl” include those described as specific examples of “6- to 8-membered heterocycloalkyl”.

In the present invention, “6- to 8-membered heterocycloalkyl” means a saturated heterocyclic group composed of 6 to 8 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. The heterocycloalkyl may be monocyclic, bicyclic, or spiro-cyclic 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 particularly 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.

In the present invention, “3- to 6-membered heterocycloalkyl” means a saturated heterocyclic group composed of 3 to 6 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. Specific examples thereof include the groups listed later in the definition of “5- or 6-membered heterocycloalkyl” as well as oxetanyl.

In the present invention, “4- to 6-membered heterocycloalkyl” means a saturated heterocyclic group composed of 4 to 6 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. Specific examples thereof include the groups listed later in the definition of “5- or 6-membered heterocycloalkyl”.

In the present invention, “5- or 6-membered heterocycloalkyl” means a saturated heterocyclic group composed of 5 or 6 ring-constituting atoms containing one to three heteroatoms selected from O, S, and N. Specific examples of the heterocycloalkyl include piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.

In the present invention, “3- to 6-membered oxacycloalkyl” means a saturated heterocyclic group composed of 3 to 6 ring-constituting atoms containing one or two oxygen atoms. Specific examples thereof include oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

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

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

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

In the present invention, “5- or 6-membered heterocycloalkyloxy” 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- to 6-membered heterocycloalkyloxy” means a 3- to 6-membered heterocycloalkyl-O— group. In this context, 3- to 6-membered heterocycloalkyl is as defined above.

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

When Re (or Rx) is 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra (or Ry), this group contains, for example, one to three nitrogen atoms as ring-constituting groups.

When Ra (or Ry) is 5- to 10-membered heterocycloalkyloxy, 3- to 6-membered heterocycloalkyloxy, or 4- to 6-membered heterocycloalkyloxy, this group contains, for example, one to three oxygen atoms or one nitrogen atom as ring-constituting groups. Examples of the heterocycloalkyloxy group include tetrahydropyranyloxy, oxetanyloxy, pyrrolidinyloxy, azetidinyloxy, and piperidinyloxy.

When R¹⁰(or R¹¹⁰) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, preferably a nitrogen atom and an oxygen atom, as ring-constituting groups. When R¹⁰(or R¹¹⁰) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, this group is preferably morpholinyl, homomorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, or tetrahydrofuranyl, more preferably morpholinyl. These groups are each optionally substituted with the substituent(s) described as substituents for the corresponding heterocycloalkyl group.

When R¹¹(or R¹¹¹) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom and an oxygen atom as ring-constituting groups.

When R¹¹(or R¹¹¹) is C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 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 each optionally substituted with the substituent(s) described as substituents for the corresponding cycloalkyl or heterocycloalkyl group.

When R¹²(or R¹¹²) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-constituting groups.

When R¹²(or R¹¹²) is 5- to 10-membered heteroaryl or 5- or 6-membered heteroaryl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-constituting groups. Further preferably, this group contains one nitrogen atom as a hetero atom.

When R¹²(or R¹¹²) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 3- to 6-heterocycloalkyl, 5- or 6-membered heterocycloalkyl, 5- to 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 each optionally substituted with the substituent(s) described as substituents for the corresponding heterocycloalkyl or heteroaryl group.

When R¹³(or R¹¹³) is 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, or 5- or 6-membered heterocycloalkyl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, preferably a nitrogen atom and an oxygen atom as ring-constituting groups.

When R¹³(or R¹¹³) is 4- to 10-membered heterocycloalkyl, 5- to 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 each optionally substituted with the substituent(s) described as substituents for the corresponding heterocycloalkyl group.

When R¹⁰(or R¹¹⁰), R¹¹(or R¹¹¹), R¹²(or R¹¹²), R¹³(or R¹¹³), or R¹⁵(or R¹¹⁵) is C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl, 5- or 6-membered heterocycloalkyl (these heterocycloalkyl groups are each optionally substituted with one or more substituents selected from substituents described as substitutents for the corresponding heterocycloalkyl group, such as oxo, a halogen atom, C_1-4alkyl (wherein the C_1-4alkyl group is optionally substituted with one or more hydroxy groups)), or 5- to 10-membered heteroaryl, this cycloalkyl group is preferably cyclopentyl, cyclohexyl, or cyclobutyl (these groups are each optionally substituted with one or more hydroxy groups); this heterocycloalkyl group is preferably tetrahydrofuranyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, homopiperazinyl, azetidinyl, or tetrahydropyranyl (these groups are each optionally substituted with one or more of the 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 (these groups are each optionally substituted with one or more of the substituents described above); and the heteroaryl group is more preferably pyridinyl.

When Ar¹(or Ar¹⁰¹) is 5- to 10-membered heteroaryl or 5- to 6-membered heteroaryl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting groups. Ar¹(or Ar¹⁰¹) is optionally substituted with one to three substituents selected from Rb (or Rz¹; the same holds true for the description below), Rc (or Rz²; the same holds true for the description below), and Rd (or Rz³; the same holds true for the description below), i.e., optionally substituted with Rb, Rc, or Rd, by Rb and Rc, Rc and Rd, or Rb and Rd, or by Rb, Rc, and Rd.

When Rd (or Rz³) is 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴(or R¹¹⁴), this group contains, for example, one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, as ring-constituting groups.

When Rd (or Rz³) is 5- to 10-membered heteroaryl or 5- to 6-membered heteroaryl optionally substituted with one or more substituents R¹⁴(or R¹¹⁴), this group contains, for example, one to three heteroatoms selected from a nitrogen atom and a sulfur atom as ring-constituting groups.

When R¹⁴(or R¹¹⁴; the same holds true for the description below) is 5- to 10-membered heterocycloalkyl, this group contains, for example, one to three heteroatoms selected from a nitrogen atom and an oxygen atom as ring-constituting groups. When R¹⁴is 5- to 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, particularly preferably 2-oxa-6-azaspiro[3.3]heptyl.

When Re (or Rx) is C_6-10aryl (for example phenyl) optionally substituted with one or more substituents Ra (or Ry) or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra (or Ry), this group is substituted with, for example, 1 to 4 substituents Ra (or Ry), preferably 1 to 3 substituents Ra (or Ry).

When R¹⁰(or R¹¹⁰; the same holds true for the description below), R¹¹(or R¹¹¹; the same holds true for the description below), R¹²(or R¹¹²; the same holds true for the description below), R¹³(or R¹¹³; the same holds true for the description below), or R¹⁵(or R¹¹⁵; the same holds true for the description below) is C_1-6alkoxy optionally substituted with one or more hydroxy groups, this group is substituted with, for example, 1 to 5 hydroxy groups, preferably 1 to 4 hydroxy groups.

When R¹⁰, R, R¹², R¹³, or R¹⁵is 5- to 10-membered heterocycloalkyl optionally substituted with one or more oxo groups, this group is substituted with, for example, 1 to 3 oxo groups, preferably 1 or 2 oxo groups.

When R¹⁰, R¹¹, R¹², R¹³, or R¹⁵is C_3-6cycloalkyl optionally substituted with one or more hydroxy groups, this group is substituted with, for example, 1 to 3 hydroxy groups, preferably 1 or 2 hydroxy groups.

When Rb, Rc, or Rd is 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴, this group is substituted with, for example, 1 to 4 substituents R¹⁴, preferably 1 to 3 substituents R¹⁴.

When R⁴is C_6-10aryl optionally substituted with one or more substituents Rg, this C_6-10aryl group is preferably phenyl.

In the group —NR³⁹R⁴⁰, R³⁹is preferably a hydrogen atom or C_1-3alkyl, more preferably methyl. R⁴⁰is preferably C_1-3alkyl, C_1-3alkoxy-substituted C_1-4alkyl, a group —CH((CH₂)_v1COOR⁵⁷)—(CH₂)_v2—COOR⁵⁷, 4- to 6-membered heterocycloalkyl, a group —(CH₂)_w—SO₃H, or a group —(CH₂)_x1—CH(COOH)—(CH₂)_x2—SO₃H, more preferably methoxyethyl, 2-methoxy-1,1-dimethylethyl, 2-methoxy-2-methyl-1-propyl, a group —C₂H₃-(COOH)₂, a group —C₃H₅-(COOH)₂, oxetanyl, methyl, a group —C₂H₄—SO₃H, or a group —CH(COOH)—CH₂—SO₃H. Examples of the group —NR³⁹R⁴⁰include N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino. In this context, “[N—((C_1-3alkoxy)C_1-4alkyl)-N—(C_1-3alkyl)amino]” is as defined above. The group —NR³⁹R⁴⁰is 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, a group —NH—CH(COOH)—CH₂(COOH), a group —NH—CH(CH₂COOH)—CH₂COOH, N-oxetanyl-N-methylamino, dimethylamino, a group —NH—C₂H₄—SO₃H, or a group —NH—CH(COOH)—CH₂—SO₃H.

In the group —(O(CH₂)_q1)_q2—NR⁴¹R⁴², q1 is preferably 2, and q2 is preferably an integer selected from 2 to 5. R⁴¹is preferably a hydrogen atom or methyl, and R⁴²is preferably C_1-6alkyl (preferably n-hexyl) substituted with 1 to 5 hydroxy groups (preferably 5 hydroxy groups) or methoxyethyl.

In the group —(O(CH₂)_r1)_r2—C(O)NR⁴³R⁴⁴, r1 is preferably 2 or 3, and r2 is preferably 1. R⁴³is preferably methyl. R⁴⁴is preferably C_1-6alkyl (preferably n-hexyl) substituted with 1 to 5 hydroxy groups (preferably 5 hydroxy groups).

The compound of the formula (I) wherein R¹and R⁵together with the carbon atom to which they are attached form a C_3-6saturated carbocyclic ring can be represented by the following formula (I-a) or (I-b):

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The group —(CH₂)_q— wherein q is 0 means a single bond.

In the present invention, the compound of the formula (I) wherein R³is C_1-4alkyl substituted with Re, which can be represented by the formula (I-c) shown below. In the present invention, the compound of the formula (I) wherein R³is C_1-4alkyl substituted with Re, Re is substituted with one to three substituents Ra, and the one to three substituents Ra 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 can be represented by the formula (I-d) shown below.

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In the formula (I-c), n1 is an integer selected from 1 to 4; n2 is an integer selected from 0 or more; and R¹, R⁴, R⁵, Ar¹, Ra, Rb, Rc, Rd, and Re are as defined in any of (1-1) to (1-48), (2-1) to (2-25), (3-1) to (3-12), (4-1) to (4-12), (5-1) to (5-12), and (6-1) to (6-10). In the formula (I-d), n3, n4, and n5 are each independently an integer selected from 0 and 1, provided that at least one of n3, n4, and n5 is 1; n1 is as defined above; R¹, R⁴, R⁵, Ar1, Rb, Rc, Rd, and Re are as defined in any of (1-1) to (1-48), (2-1) to (2-25), (3-1) to (3-12), (4-1) to (4-12), (5-1) to (5-12), and (6-1) to (6-10).

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

In the present invention, the phrase “optionally substituted with” or “substituted with” means “optionally substituted with one substituent” or “substituted with one substituent” respectively unless a number of substituents (for example, “one or more”, “one to three”, “one or two”, “two” or “one”) is specified. 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 the salt of the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) include acid-addition salts and base-addition salts. Examples of the 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 the base-addition salts 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 each produced by the contact of the compound with an acid or a base available in pharmaceutical production.

In the present invention, the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) or the salt thereof may be an anhydrate or may form a solvate such as a hydrate. In this context, the “solvate” refers to a solid formed by a complex of the compound molecule and a solvent molecule and refers to, for example, a hydrate formed from water as a solvent. The solvate other than the hydrate includes a solid containing an alcohol (e.g., methanol, ethanol, and n-propanol), dimethylformamide, or the like.

The compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) and the salt thereof may be found as some tautomers, for example, keto and enol forms, imine and enamine forms, and mixtures thereof. Such tautomers are present as a tautomeric mixture in a solution. In a solid form, one of the tautomers is usually predominant. Although one of the tautomers may be described herein, all tautomers of the compound of the present invention are included in the present invention.

The present invention further includes all stereoisomers (e.g., enantiomers and diastereomers (including cis and trans geometric isomers)) of the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d), racemates of the isomers, and other mixtures. The compound of the present invention may have, for example, one or more asymmetric atoms. The compound of the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such a compound.

The compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) may be obtained in a free form. In this case, the free compound can be converted by a routine method to the salt that may be formed by the compound or to the hydrate or the solvate of the compound or the salt.

Alternatively, the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) may be obtained as the salt, hydrate, or solvate of the compound. In this case, this form can be converted to the free form of the compound according to a routine method.

Each element constituting the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) may be any isotope. The present invention encompasses a compound of the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) containing such an isotope. The isotope in the compound refers to a variant of the element in which at least one atom is replaced with an atom with the same atomic number (the same number of protons) and a different mass number (total number of protons and neutrons). Examples of the isotope contained in the pharmaceutical drug of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom including ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl. Particularly, a radioisotope, such as ³H or ¹⁴C, which undergoes radioactive decay are useful in, for example, the in vivo histological distribution tests of the pharmaceutical drug or the compound. Stable isotopes rarely vary in abundance without decay and are also free from radioactivity. These stable isotopes can therefore be used with safety. The isotope in the compound serving as an active ingredient in the pharmaceutical drug of the present invention can be converted according to a routine method by the replacement of a reagent used in synthesis with a reagent containing the corresponding isotope.

The compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) may be administered in the form of a prodrug. The present invention also includes such a prodrug of the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d). In this context, the “prodrug” of the present invention means a derivative of the compound of the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) that is converted after administration to the compound of the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) or the pharmaceutically acceptable salt thereof through enzymatic or nonenzymatic 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 the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d).

The prodrug is converted to, for example, a desired pharmaceutical formulation at a particular pH or by the action of an enzyme. The prodrug is typically a compound that forms a free acid in vivo and a compound having a hydrolyzable ester group. Such a hydrolyzable ester group is, for example, but not limited to, a group represented by the formula —COORx, wherein Rx is selected from C_1-4alkyl, C₂-7 alkanoyloxymethyl, 1-(C_4-9alkanoyloxy)ethyl, 1-methyl-1-(C_5-10alkanoyloxy)-ethyl, (C_3-6alkoxy)carbonyloxymethyl, 1-[(C_4-7alkoxy)carbonyloxy]ethyl, 1-methyl-1-[(C_5-8alkoxy)carbonyloxy]ethyl, N—[(C_3-9alkoxy)carbonyl]aminomethyl, 1-(N—[(C_4-10alkoxy)carbonyl]amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, [N,N-di(C_1-2alkyl)amino]C_2-3alkyl (e.g., N,N-dimethylaminoethyl), (carbamoyl)C_1-2alkyl, [N,N-di(C_1-2alkyl)carbamoyl]C_1-2alkyl, (piperidino)C₂-3 alkyl, (pyrrolidino)C₂-3 alkyl, and (morpholino)C₂-3 alkyl.

Pharmaceutical Drug of the Present Invention

One aspect of the present invention provides a pharmaceutical drug and a pharmaceutical composition containing the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) or the salt thereof, or the solvate of the compound or the salt. In this invention, “pharmaceutical composition” refers to a mixture containing certain amounts or proportions of specific ingredients.

The pharmaceutical drug of the present invention contains the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d) as an active ingredient and further contains a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” used herein means one or more compatible solid or liquid excipients or encapsulating materials that are suitable for administration to mammals. The term “pharmaceutically acceptable” used herein means pharmaceutically available from the viewpoint of efficacy, safety, etc. The pharmaceutically acceptable carrier used is suitable for administration to an animal, preferably a mammal, to be treated, from the viewpoint of safety and has sufficiently high purity.

Examples of a material that may be used as the 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 carboxymethylcellulose sodium, ethylcellulose, and methylcellulose; tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; plant oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cacao oil; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as lecithin; colorants; flavors; tableting agents; stabilizers; antioxidants; antiseptics; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The compound of the present invention may be used as a NaPi-IIb inhibitor or a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, or chronic renal failure. In this case, or in a case where the pharmaceutical composition of the present invention may be used, examples of an administration method thereof include oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical and local (drip, powder, ointment, gel, or cream) routes, and inhalation (into the oral cavity or using nasal sprays). Examples of the dosage form thereof include tablets, capsules, granules, powders, pills, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions charged in containers adapted to division into individual doses. Alternatively, the dosage form may be adapted to various administration methods encompassing controlled-release formulations as in subcutaneous implantation.

These preparations are produced by a well known method using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, corrigents, and diluents.

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

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

Examples of the binders can include polyvinylpyrrolidone, Macrogol, and the same compounds as those listed as the excipients.

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

Examples of the stabilizers can include: p-hydroxybenzoate esters 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 the corrigents can include sweeteners, acidulants, and flavors usually used.

The liquid preparations can be produced using a solvent such as ethanol, phenol, chlorocresol, purified water, or distilled water.

Examples of the surfactants or emulsifiers can include polyoxyl 40 stearate and Lauromacrogol.

When the compound of the present invention is used as a NaPi-IIb inhibitor, PiT-1 inhibitor, PiT-2 inhibitor or a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, or chronic renal failure, the amount of the pharmaceutical drug of the present invention used differs depending on symptoms, age, body weight, relative health conditions, the presence of other medications, administration methods, etc. In the case of oral agents, a general effective amount, for example, for a patient (warm-blooded animal, particularly a human) is preferably 1 to 20 mg/kg body weight, more preferably 1 to 10 mg/kg body weight, per day in terms of the amount of the active ingredient (the compound of the present invention represented by the formula (I)). The daily dose in an adult patient having a normal body weight is in the range of preferably 60 to 1200 mg.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, in addition to an active ingredient (for example, the compound represented by the formula (I), (II), (III), (I-a), (I-b), (I-c), or (I-d)).

The pharmaceutical composition of the present invention may be used in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, or in the prevention or suppression of ectopic calcification.

Chronic kidney disease is basically classified into stages 1 to 5 according to GFR (glomerular filtration rate): GFR of 90 or more is classified as stage 1, GFR of 60 or more to less than 90 as stage 2; GFR of 30 or more to less than 60 as stage 3; GFR of 15 or more to less than 30 as stage 4; and GFR of less than 15 as stage 5 (“Clinical Practice Guidelines for CKD 2012” Japanese Journal of Nephrology, 2012; 54 (8); 1031-1189).

As one embodiment of the present invention, the pharmaceutical composition of the present invention is used for the prevention or treatment of chronic kidney disease of stages 2 to 4 classified by GFR.

The present inventors have found that, in animal models of hyperphosphatemia and chronic kidney disease, the expression level of NaPi-IIb in the gastrointestinal tract was lowered while the expression levels of PiT-1 and PiT-2 did not change, and as a result, the proportion of phosphate absorption by PiT-1 and PiT-2 with respect to the total phosphate absorption in the gastrointestinal tract became relatively high. From the findings, the present inventors have found that inhibition of PiT-1 or PiT-2 provides an excellent effect in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, or in the prevention or suppression of ectopic calcification. Further, the inventors have found that, in the prevention or treatment of a disease selected from hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and arteriosclerosis associated with vascular calcification, or in the prevention or suppression of ectopic calcification, a better effect was obtained when all of the transporters, NaPi-IIb, PiT-1, and PiT-2 were inhibited, compared to when only NaPi-IIb was inhibited.

In 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 adsorbent to prevent or treat hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and vascular calcification or to prevent or suppress ectopic calcification, the substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2 (hereinafter referred to as “transporter inhibitory substance”) and the phosphorus adsorbent may be administered simultaneously or separately. The pharmaceutical composition of the present invention may be provided in the form of a combined drug containing both a transporter inhibitory substance and a phosphorus adsorbent. Further, a medicament containing a transporter inhibitory substance and a medicament containing a phosphorus adsorbent may be provided separately and be used simultaneously or sequentially. Furthermore, the pharmaceutical composition may be provided as a kit comprising a medicament containing a transporter inhibitory substance and that containing a phosphorus adsorbent.

In the pharmaceutical composition above, in the case of providing a transporter inhibitory substance and a phosphorous adsorbent that are incorporated in different medicaments, the dosage forms of the medicaments may be the same as, or different from, each other. For example, the medicaments may be both one of parenteral preparations, injections, drops, and intravenous drips but may differ from each other in dosage form, or the medicaments may be both one of parenteral preparations, injections, drops, and intravenous drips and may be the same as each other in dosage form. In addition, one or more further preparations may be combined with the pharmaceutical composition.

In another aspect, the present invention provides 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 “transporter inhibitory substance”) as an active ingredient, and this composition is used in combination with a phosphorus adsorbent to prevent or treat hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and vascular calcification or to prevent or suppress ectopic calcification. When the pharmaceutical composition of the present invention containing a transporter inhibitory substance as an active ingredient is used in combination with a phosphorus adsorbent, the composition may be administered simultaneously with the phosphorus adsorbent. Also the composition may be administered before or after administration of the phosphorus adsorbent. In a case where a transporter inhibitory substance is administered after administration of a phosphorus adsorbent, timing of administration of the transporter inhibitory substance may be optimized by measuring the residual concentration of phosphorus adsorbent in a subject. This concentration may be determined based on the results of analysis of samples collected from the subject, through an analysis method known to those skilled in the art using a variety of separators such as chromatography.

In another aspect, the present invention provides a pharmaceutical composition that contains a phosphorus adsorbent 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 as “transporter inhibitory substance”) to prevent or treat hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, and vascular calcification or to prevent or suppress ectopic calcification. When the pharmaceutical composition containing a phosphorus adsorbent 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 also may be administered before or after administration of the transporter inhibitory substance.

In a case where a phosphorus adsorbent is administered before administration of a transporter inhibitory substance, timing of administration of the phosphorus adsorbent may be optimized by measuring the residual concentration of the phosphorus adsorbent in a subject. This concentration may be determined based on the results of analysis of samples collected from the subject, through an analysis method known to those skilled in the art using a variety of separators 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, and the like) that inhibit phosphorus absorption in the gastrointestinal tract performed by one or more sodium-dependent phosphate transporters selected from NaPi-IIb, PiT-1, and PiT-2. The term “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 the “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 a “low-molecular compound that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2” may include the compounds according to (1-1) to (1-49) or salts thereof, or solvates of the compounds or the salts, which are described as components of pharmaceutical compositions. Other specific examples may include the compounds disclosed in WO2012/006475, WO2011/136269, WO2013/062065, WO2013/082756, WO2013/082751, and WO2013/129435, or salts thereof, or solvates of the compounds or the salts.

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

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(wherein Ac means an acetyl group)

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With regard to the route of administration of a substance that inhibits one or more transporters selected from NaPi-IIb, PiT-1, and PiT-2, either of an oral or parenteral route can be preferably used, but an oral route is more preferable. The dosage form used for oral administration may be selected as appropriate from any forms, such as liquid, powder, granular, tablet, enteric coated, and capsule dosage forms, for example. Such a dosage form is prepared as a drug product by a method known to those skilled in the art. For example, an active ingredient is first combined as appropriate with a pharmacologically acceptable carrier or medium, specifically including but not limited to sterile water or normal saline, plant oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, vehicle, antiseptic, or binder, and then the combined components are blended into a unit dosage form required in generally acceptable pharmaceutical practice, and formulated into a drug product by a formulation process, such as freeze-drying or tableting.

Phosphorus Adsorbent

In the present invention, a “phosphorus adsorbent” includes any phosphorus adsorbents that are known, or suggested, as suppressing phosphorus absorption in the gastrointestinal tract by adsorbing phosphorus. The “phosphorus adsorbent” includes, but not limited to: nonmetallic polymer adsorbents typified by bixalomer, sevelamer carbonate, and sevelamer hydrochloride; calcium salt preparations typified by precipitated calcium carbonate, calcium acetate, calcium citrate, calcium alginate, and calcium salt of keto-acid; and metallic adsorbents typified by lanthanum carbonate, aluminum hydroxide, iron preparations (sucroferric oxyhydroxide (polynuclear iron(III) oxide hydroxides), polynuclear iron(III)-oxyhydroxide), Fermagate (magnesium iron hydroxycarbonate), and ferric citrate hydrate).

With regard to the route of administration of a phosphorus adsorbent used in the present invention, either of an oral or parenteral route can be preferably used, but an oral route is more preferable. The dosage form used for oral administration may be selected as appropriate from any forms, such as liquid, powder, granular, tablet, enteric coated, and capsule dosage forms, for example. A phosphorus adsorbent having such a dosage form is prepared as a drug product by a method known to those skilled in the art. For example, a phosphorus adsorbent is first combined as appropriate with a pharmacologically acceptable carrier or medium, specifically including but not limited to sterile water or normal saline, plant oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, vehicle, antiseptic, or binder, and then the combined components are blended into a unit dosage form required in generally acceptable pharmaceutical practice, and formulated into a drug product by a formulation process, such as freeze-drying or tableting.

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 “transporter inhibitory substance”) and a phosphorus adsorbent means that the transporter inhibitory substance and the phosphorus adsorbent are administered or used (hereinafter simply referred to as “administered”) in combination, and thus the order of administration, interval of administration, or the like should not be construed in a limited manner. Further, a transporter inhibitory substance and a phosphorus adsorbent may be combined and used as a kit. Furthermore, in a case where a transporter inhibitory substance and a phosphorus adsorbent are used in combination according to the present invention, the dose of each of the two drugs can be reduced, if desired, compared to that required in a case where one of them is administered alone.

In a case where a transporter inhibitory substance and a phosphorus adsorbent are separately administered, the interval of administration of the transporter inhibitory substance and the phosphorus adsorbent is not specifically limited and may be determined taking into consideration factors such as the administration route or dosage form. For example, the interval may be 0 hour to 168 hours, preferably, 0 hour to 72 hours, more preferably, 0 hour to 24 hours, and yet more preferably, 0 hour to 12 hours. Also, not only the factors such as the administration route or dosage form, but also the residual concentration of each of the transporter inhibitory substance and the phosphorus adsorbent in a subject may be considered. More specifically, in a case where a phosphorus adsorbent is administered before administration of a transporter inhibitory substance, the transporter inhibitory substance may be administered at a point when the detected residual concentration of phosphorus adsorbent in the subject reaches a level at which the desired effect by the phosphorus adsorbent may be achieved. This concentration may be determined based on the results of analysis of samples collected from the subject, through an analysis method known to those skilled in the art using a variety of separators such as chromatography.

Conversely, in a case where a transporter inhibitory substance is administered before administration of a phosphorus adsorbent, the phosphorus adsorbent may be administered at a point when the detected residual concentration of transporter inhibitory substance in a subject reaches a level at which the desired effect by the phosphorus adsorbent may be achieved. This concentration may be determined based on the results of analysis of samples collected from the subject, through an analysis method known to those skilled in the art using a variety of separators such as chromatography.

In a case where the pharmaceutical composition of the present invention is provided in the form of a combined drug containing both a transporter inhibitory substance and a phosphorus adsorbent, the content of each of the transporter inhibitory substance and the phosphorus adsorbent is not specifically limited. With regard to the route of administration of the combined drug, either of an oral or parenteral route can be preferably used, but an oral route is more preferable. The dosage form for oral administration may be selected as appropriate from any forms, such as liquid, powder, granular, tablet, enteric coated, and capsule dosage forms, for example. A phosphorus adsorbent having such a dosage form is prepared as a drug product by a method known to those skilled in the art.

Hereinafter, general methods for producing the compound of the present invention and Examples will be shown.

General Synthesis Method

The compound of the present invention can be synthesized by various methods.

Some of the methods will be described with reference to schemes shown below. These schemes are provided for illustrative purposes, and the present invention is not limited by chemical reactions and conditions described herein. Although some substituents are excluded from the schemes shown below for easy understanding, such exclusion is not intended to limit the disclosure of the schemes. Typical compounds of the present invention can be synthesized using appropriate intermediates, compounds known in the art, and reagents. In the formulas of the general synthesis methods described below, variable groups represented by R¹, R², etc. and variables represented by n, etc. have the same meanings as those of the variable groups represented by R¹, R², etc. and the variables represented by n, etc. in the compounds represented by general formulas defined herein.

The compound of the present invention can be synthesized by production methods shown below.

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wherein R²¹represents C_1-3alkyl; R²²represents C_1-5alkyl; and R³═O (2) represents aldehyde or ketone formed by the conversion of a carbon atom at the linkage position of alkyl represented by R³to carbonyl.

Step 1 involves reacting a compound of the formula (1) with aldehyde or ketone (2) in an appropriate solvent such as methanol or dichloromethane to synthesize a compound (3). The reaction is performed at a temperature of, for example, 0° C. to room temperature for a time of, for example, 0.5 hours to 24 hours. The obtained hydrazone derivative (3) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

A large number of applicable methods have been reported as to the synthesis method for the hydrazine (1) shown in Scheme 1 (this reaction can be performed with reference to, for example, Synthetic communications, 40, 654-660; 2010, Journal of Heterocyclic Chemistry, 24 (3), 725-731; 1987, and Synthesis, (6), 423-424; 1979).

Step 2 involves reducing the hydrazone (3) in the presence of a reducing agent such as sodium cyanoborohydride or borane pyridine in an appropriate solvent such as methanol or acetic acid to obtain hydrazine (4). The reaction is performed at a temperature of, for example, 0° C. to 50° C. for a time of, for example, 0.5 hours to 60 hours. The obtained hydrazine (4) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

Step 3 involves reacting the hydrazine (4) with half ester (5) using a condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride n-hydrate (DMT-MM), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop), or 1-propanephosphonic acid cyclic anhydride (T3P) in an appropriate solvent such as dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, or ethyl acetate. The reaction is performed at a temperature of, for example, 0° C. to 50° C. for a time of, for example, 0.5 hours to 24 hours. The obtained ester form (6) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

The half ester (5) shown in Scheme 1 can be synthesized from Meldrum's acid and an alcohol (this reaction can be performed with reference to, for example, Organic Letters, 7 (3), 463-465; 2005).

Step 4 involves cyclizing the ester form (6) using a base such as potassium carbonate, cesium carbonate, sodium methoxide, or sodium hydride in an appropriate solvent such as methanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, diethyl ether, or tetrahydrofuran. The reaction is performed at a temperature of, for example, 0° C. to 110° C. for a time of, for example, 0.5 hours to 24 hours. The obtained cyclized form (7) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

Step 5 involves reacting the cyclized form (7) with various amines (8) in an appropriate solvent such as benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide. The reaction is performed at a temperature of, for example, 50° C. to 120° C. for a time of, for example, 0.5 hours to 5 hours. The obtained amide form (formula I) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

R²¹is preferably methyl, and R²²is preferably methyl or i-butyl.

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

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wherein R²²is as defined in Scheme 1.

The keto form (9) as a product in Step 1 can be synthesized by the decarboxylation of an ester form (7) (this reaction can be performed with reference to, for example, Synthesis, (15), 2487-2491; 2009).

Step 2 involves reacting the keto form (9) with isocyanate in the presence of a base such as sodium hydride, potassium carbonate, or cesium carbonate in an appropriate solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran. The reaction is performed at a temperature of, for example, 0° C. to 50° C. for a time of, for example, 0.5 hours to 5 hours. The obtained amide form (formula I) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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

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wherein R²¹is as defined in Scheme 1.

Step 1 involves reacting the hydrazine (4) with half amide (10) in the presence of a condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride n-hydrate (DMT-MM), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop), or 1-propanephosphonic acid cyclic anhydride (T3P) in an appropriate solvent such as dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, or ethyl acetate. The reaction is performed at a temperature of, for example, 0° C. to 50° C. for a time of, for example, 0.5 hours to 24 hours. The obtained amide form (11) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

The half amide (10) shown in Scheme 3 can be synthesized from Meldrum's acid and amine (this reaction can be performed with reference to, for example, Bioorganic & Medicinal Chemistry Letters, 19 (13), 3632-3636; 2009).

Step 2 involves cyclizing the amide form (11) using a base such as sodium methoxide, potassium carbonate, cesium carbonate, or sodium hydride in an appropriate solvent such as methanol, N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran. The reaction is performed at a temperature of, for example, 0° C. to 110° C. for a time of, for example, 0.5 hours to 24 hours. The obtained compound of the formula I is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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

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Three exemplary methods of Step 1 will be shown below.

Method 1 involves debenzylating a 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 an appropriate solvent such as methanol, ethyl acetate, N,N-dimethylformamide, or N,N-dimethylacetamide in a hydrogen atmosphere. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 1 hour to 24 hours. Method 2 involves reacting the compound (12) in the presence of an oxidizing agent such as 2,3-dichloro-5,6-dicyano-p-benzoquinone or ammonium hexanitratocerate(IV) in an appropriate solvent such as dichloromethane or acetonitrile. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 1 hour to 60 hours. Method 3 involves reacting the compound (12) in the presence of an organic acid such as trifluoroacetic acid or trifluoromethanesulfonic acid in an appropriate solvent such as dichloromethane or methanol. The reaction is performed at a temperature of, for example, 0° C. to the boiling point of the solvent for a time of, for example, 0.5 hours to 5 hours. The obtained NH form (13) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

Step 2 involves reacting the NH form (13) with an alkylating agent such as alkyl halide or alkyl sulfonate in the presence of an appropriate base such as sodium hydride, potassium t-butoxide, or potassium pentoxide in an appropriate solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or dimethyl sulfoxide. The reaction is performed at a temperature of, for example, 0° C. to the boiling point of the solvent for a time of, for example, 0.5 hours to 24 hours. The obtained compound of the formula I is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

In —OSO₂R²³shown in this scheme, R²³is C_1-5alkyl 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 R²³include methyl, trifluoromethyl, phenyl, and 4-methylphenyl.

The compound of the formula I can also be synthesized by alkylation as shown in Scheme 5 (Method E).

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wherein R²²is as defined in Scheme 1.

The reaction of Step 1 of Scheme 5 (Method E) can be pursued in the same way as in Step 1 of Scheme 4 (Method D).

The reaction of Step 2 of Scheme 5 (Method E) can be pursued in the same way as in Step 2 of Scheme 4 (Method D). The compound of the formula I can be obtained in the same way as in Step 5 of Scheme 1 from the obtained ester form (7).

Side chain introduction method

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wherein n is an integer selected from 1 to 10, and R²⁴is C_1-8alkoxy optionally substituted with one or more substituents R¹².

The method of Scheme 6 (Method F) involves reacting a phenol derivative (16) with an alkylating agent such as alkyl halide or alkyl sulfonate in the presence of an appropriate base such as sodium hydride, potassium carbonate, cesium carbonate, potassium t-butoxide, or potassium pentoxide in an appropriate solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-acetamide, dimethyl sulfoxide, or acetone. The reaction is performed at a temperature of, for example, 0° C. to the boiling point of the solvent for a time of, for example, 0.5 hours to 12 hours. The obtained compound represented by the formula III is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography. The compound obtained in Scheme 6 can be subjected, if necessary, to the deprotection reaction of various protective groups and other procedures to synthesize a derivative.

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wherein n and R²⁴are as defined in Scheme 6.

The method of Scheme 7 (Method G) involves reacting a phenol derivative (16) with various alcohols using an appropriate Mitsunobu reagent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N,N,N′,N′-tetraisopropylazodicarboxamide (TIPA), 1,1′-(azodicarbonyl)dipiperidine (ADDP), or N,N,N′,N′-tetramethylazodicarboxamide (TMAD) in the presence of an appropriate trivalent organic phosphorus reagent such as triphenylphosphine or tributylphosphine in an appropriate solvent such as dichloromethane, tetrahydrofuran, acetonitrile, toluene, or benzene. The reaction is performed at a temperature of, for example, 0° C. to the boiling point of the solvent for a time of, for example, 0.5 hours to 24 hours. The obtained compound represented by the formula III is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography. The compound obtained in Scheme 7 can be subjected, if necessary, to the deprotection reaction of various protective groups and other procedures to synthesize a derivative.

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wherein n is an integer selected from 1 to 10, and R²⁵is (C_1-4alkoxy)carbonyl, C_1-10alkyl optionally substituted with one or more substituents R¹⁰, C_2-10alkynyl optionally substituted with one or more substituents R¹¹, or C_1-4alkylthio optionally substituted with one or more substituents R¹³.

The method of Scheme 8 (Method H) involves reacting a bromobenzene or iodobenzene derivative (17) using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) (Pd(Ph₃P)₄), tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (PdCl₂(dppf).CH₂Cl₂), palladium(II) acetate (Pd(OAc)₂), or dichlorobis(triphenylphosphine)palladium(II) (PdCl₂(Ph₃P)₂) supplemented, if necessary, with a phosphine ligand such as triphenylphosphine (Ph₃P), tri-t-butylphosphine (tBu₃P), or tri-o-tolylphosphine ((o-tol)₃P), a copper catalyst such as copper(I) iodide, and an appropriate base such as sodium carbonate, triethylamine, or potassium carbonate in an appropriate solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, benzene, 1,2-dimethoxyethane, 1,4-dioxane, ethanol, or acetonitrile to introduce thereinto, for example, sulfur, alkane, alkyne, or alkoxycarbonyl. When R²⁵is (C_1-4alkoxy)carbonyl, for example, carbon monooxide and C_1-4alcohol can be used as a reagent in the reaction. When R²⁵is C_1-10alkyl optionally substituted with one or more substituents R¹⁰or C_2-10alkynyl, for example, acetylene or (C_1-8alkyl)-C≡CH can be used as a reagent in the reaction. When R²⁵is C_1-4alkylthio optionally substituted with one or more substituents R¹³, for example, C_1-4alkylmercaptan can be used as a reagent in the reaction. The reaction is performed at a temperature of, for example, 0° C. to the boiling point of the solvent for a time of, for example, 0.5 hours to 60 hours. The obtained compound represented by the formula IV is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography. The compound obtained in Scheme 8 can be subjected, if necessary, to the hydrogenation reaction of a double bond and a triple bond, the oxidation reaction or alkylation of a sulfur atom, the deprotection reaction of various protective groups, and other procedures to synthesize a derivative.

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wherein R²², R²³, and R²⁵are as defined in Schemes 1 and 8.

The reaction of Scheme 9 (Method I) can be pursued in the same way as in Scheme 8 with a compound (18) as a starting material. The compound of the formula IV can be obtained in the same way as in Step 5 of Scheme 1 from the obtained ester form (19).

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wherein

Ar¹is C_6-10aryl or 5- to 10-membered heteroaryl, wherein this group is optionally substituted with Rb and/or Rc; and

Rd is selected from 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴.

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

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The method of Scheme 10 (Method J) involves reacting an aryl halide derivative (20) with aryl boronic acid, heteroaryl boronic acid, heterocycloalkyl boronic acid, aryl boronic acid ester, heteroaryl boronic acid ester, heterocycloalkyl boronic acid ester, aryltrialkyltin, heteroaryltrialkyltin, heterocycloalkyltrialkyltin, or the like using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) (Pd(Ph₃P)₄), tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (PdCl₂(dppf).CH₂Cl₂), or palladium(II) acetate (Pd(OAc)₂) supplemented, if necessary, with a phosphine ligand such as triphenylphosphine (Ph₃P), tri-t-butylphosphine (tBu₃P), or tri-o-tolylphosphine ((o-tol)₃P) and an appropriate base such as sodium carbonate, triethylamine, or potassium carbonate in an appropriate solvent such as tetrahydrofuran, acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane (DME), or 1,4-dioxane in a nitrogen atmosphere to introduce an aryl group thereinto. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 0.5 hours to 12 hours. The obtained bisaryl form (formula V) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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wherein

R²³is as defined above;

Ar¹and Rd are as defined in Scheme 10; and

R¹⁴is selected from cyano, C_1-4alkoxy optionally substituted with one or more halogen atoms, and —NR²⁷R²⁸(R²⁷and R²⁸are each independently selected from optionally (C_1-3alkoxy)carbonyl-substituted C_1-4alkyl).

The method of Scheme 11 (Method K) involves reacting heteroaryl halide or sulfonic acid heteroaryl ester (21) with a nucleophile such as amine, nitrile, or alcohol, if necessary in the presence of a base such as sodium hydride, sodium alkoxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, or diazabicycloundecene (DBU) in an appropriate solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or dimethyl sulfoxide. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 0.5 hours to 24 hours. The obtained bisaryl form (formula VI) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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wherein

R²³is as defined in Scheme 11;

Rd is 5- to 10-membered heterocycloalkyl, C_6-10aryl, or 5- to 10-membered heteroaryl; and

Y is selected from cyano, C_1-4alkoxy optionally substituted with one or more halogen atoms, and —NR²⁷R²⁸(R²⁷and R²⁸are each independently selected from optionally (C_1-4alkoxy)carbonyl-substituted C_1-4alkyl).

The method of Scheme 12 (Method L) involves reacting heteroaryl halide, sulfonic acid heteroaryl ester, or nitroheteroaryl (22) having an electron-withdrawing substituent (EWG) with a nucleophile such as amine, nitrile, or alcohol, if necessary in the presence of a base such as sodium hydride, sodium alkoxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, or diazabicycloundecene (DBU) in an appropriate solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, or an alcoholic solvent. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 0.5 hours to 24 hours. The obtained bisaryl form (the formula VII) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

Starting material synthesis

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wherein Ar¹and Rd are as defined in Scheme 10.

According to Scheme 13 (Method M), the arylamine (8) (wherein Rd is 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R¹⁴, C_6-10aryl optionally substituted with one or more substituents R¹⁴, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents R¹⁴) for use in the reaction of Step 5 of Scheme 1 is synthesized. This method involves reacting aryl halide (23) or (26) with aryl boronic acid, aryl boronic acid ester, aryltrialkyltin, or the like in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) supplemented, if necessary, with a base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydroxide in an appropriate solvent such as water, toluene, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, 1,2-dimethoxyethane, or tetrahydrofuran. The reaction is performed at a temperature of, for example, room temperature to the boiling point of the solvent for a time of, for example, 0.5 hours to 24 hours. The obtained bisaryl form (25) or (28) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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wherein R¹, R⁴, R⁵, and R²¹are as defined above.

According to Scheme 14 (Method N), the hydrazine for use in the reaction of Step 1 of Scheme 1 is synthesized. The compound (1) can be synthesized with reference to, for example, Bioorganic & Medicinal Chemistry Letters 13 (2003) 2413-2418.

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wherein R²⁶is benzyl, methyl, or t-butyl, and R¹, R⁴, and R⁵are as defined above.

According to Scheme 15 (Method 0), the amine (34) for synthesis of the hydrazine (1) for use in the reaction of Step 1 of Scheme 1 is synthesized.

Step 1 involves N-alkylating a carbamate-protected amino acid using an appropriate base reagent such as sodium hydride, potassium carbonate, or cesium carbonate or a silver salt such as silver(I) oxide in the presence of alkyl halide in an appropriate solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or dimethyl sulfoxide. The reaction is performed at a temperature of, for example, 0° C. to 80° C. for a time of, for example, 0.5 hours to 5 hours. The obtained N-alkyl form (33) is isolated by a general technique and may be purified, if necessary, by crystallization or chromatography.

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

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wherein R¹, R⁴, R⁵, and R²⁶are as defined above.

According to Scheme 16 (Method P), the carbamate-protected amino acid (36) for synthesis of the compound (33) for use in the reaction of Step 1 of Scheme 15 is synthesized. The compound (36) can be synthesized using Curtius rearrangement for carboxylic acid (35) (this reaction can be performed with reference to, for example, J. Org. Chem., 1994, 59 (26), 8215-8219). The compound (33) can be synthesized in the same way as in Step 1 of Scheme 15.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples. However, the present invention is not limited by these examples.

EXAMPLES

The contents of the present invention will be further described with reference to Examples and Reference Examples below. However, the present invention is not limited by the contents of these examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using methods known in the art. Each compound is purified by HPLC using AutoPurification HPLC/MS System (manufactured by Waters Corp.). ¹H-NMR or ¹³C-NMR spectra were measured using Me₄Si as an internal standard and Agilent 400-MR (manufactured by Agilent Technologies, Inc.) or AVANCE3 Cryo-TCI (Bruker Corp.) (s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddd=double double doublet, dt=double triplet, td=triple doublet, and m=multiplet). Mass spectrometry was performed using a mass spectrometer SQD (manufactured by Waters Corp.), 2020 (manufactured by Shimadzu Corp.), or 2010EV (manufactured by Shimadzu Corp.). Retention time measurement and mass spectrometry in LCMS were performed using the following apparatuses and analysis conditions:

TABLE 1

LCMS analysis

condition No.
Apparatus
Column
Mobile phase and gradient

SMD-TFA05
nexera/2020
Kinetex
0.05% TFA/0.05% TFA MeCN =

2.1 mmI.D. × 50 mm
95/5 → 0/100(1.5 min) →

0/100(0.5 min), 1 mL/min

SMD-TFA50
nexera/2020
Kinetex
0.05% TFA/0.05% TFA MeCN =

2.1 mmI.D. × 50 mm
50/50 → 0/100(1 min) →

0/100(1 min), 1 ml/min

SMD-FA05
nexera/2020
Ascentis Express
H₂O(0.1% FA)/MeCN(0.1% FA)

C18
95/5 → 0/100(1.5 min) →

2.1 mmI.D. × 50 mm
100(0.6 min), 1 mL/min

SQD-AA05
UPLC/SQD
Ascentis Express
10 mMAcONH₄/MeOH =

C18
95/5 → 0/100(1 min) →

2.1 mmI.D. × 50 mm
100(0.4 min), 1 mL/min

SQD-AA50
UPLC/SQD
Ascentis Express
10 mMAcONH₄/MeOH =

C18
50/50 → 0/100(0.7 min) →

2.1 mmI.D. × 50 mm
100(0.7 min), 1 mL/min

SQD-FA05
UPLC/SQD
Ascentis Express
H₂O(0.1% FA)/MeCN(0.1% FA) =

C18
95/5 → 0/100(1 min) →

2.1 mmI.D. × 50 mm
100(0.4 min), 1 mL/min

SQD-FA50
UPLC/SQD
Ascentis Express
H₂O(0.1% FA)/MeCN(0.1% FA) =

C18
50/50 → 0/100(0.7min) →

2.1 mmI.D. × 50 mm
100(0.7 min), 1 mL/min

SMD-AA05
nexera/2020
Ascentis Express
10 mM AcONH4/MeOH =

C18
95/5 → 0/100(1.5 min) →

2.1 mmI.D. × 50 mm
100(0.7 min), 1 mL/min

QC-SMD-
nexera/2020
Acquity
0.05% TFA/0.05% TFA MeCN =

TFA05

2.1 mmI.D. × 50 mm
95/5 → 0/100(1.5 min) →

0/100(0.5 min), 1 ml/min

Ph-SMD-TFA05
UFLC-MS
shim-pack XR-ODS
0.05% TFA/0.05% TFA MeCN =

2010EV
3.0 mmI.D. × 50 mm
95/5 → 0/100(2 min) →

0/100(1.1 min), 1 mL/min

ZQ-01
2525BGM/
Chromolith Flash
10 mM AcONH4/MeOH =

2996PDA/
RP-18e 4.6 mmI.D. ×
95/5 → 0/100(3 min) →

ZQ2000
25 mm
100(2 min), 2 mL/min

SQD-TFA05
UPLC/SQD
Ascentis Express
H₂O0.1% TFA)/

C18
MeCN(0.1% TFA) =

2.1 mmI.D. × 50 mm
95/5 → 0/100(1 min) →

100(0.4 min), 1 mL/min

A compound having a C═N bond in a hydrazone structural formula represented by the following formula

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was used in next reaction without particular confirmation of whether the compound was in a cis form or a trans form or a mixture thereof.

Example 1
(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 Step

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

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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. After the reaction mixture was concentrated at reduced pressure and toluene was added, for azeotropic removal of water suspended in dichloromethane (60.4 mL), sodium nitrite (2.19 g, 31.7 mmol) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. After the reaction mixture was filtered, the resultant was concentrated at reduced pressure to obtain (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The obtained crude product was dissolved in acetic acid (30.2 mL) and water (30.2 mL), then zinc (19.7 g, 302 mmol) was added at 0° C., and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. After sodium bicarbonate was added to the reaction mixture at 0° C., methanol (60.4 mL) and 3-fluoro-benzaldehyde (3.20 mL, 30.2 mmol) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. After the reaction mixture was filtered, the resultant was concentrated at reduced pressure and then extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (5.68 g, 75%).

LCMS: m/z 251[M+H]⁺

HPLC retention time: 0.97 minutes (analysis condition SQD-AA05)

Second Step

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

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(S)-1-[(3-Fluoro-benzylidene)-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. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, then the mixture was concentrated at reduced pressure and extracted with ethyl acetate. The organic layer was washed with a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (S)-1-(3-fluoro-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The obtained crude product was dissolved in tetrahydrofuran (22.7 mL), tripotassium phosphate (9.64 g, 45.4 mmol) and chlorocarbonyl-acetic acid methyl ester (2.67 mL, 45.4 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere at room temperature for 3 hours. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (S)-1-[(3-fluoro-benzyl)-(2-methoxycarbonyl-acetyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The obtained 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 nitrogen atmosphere at 80° C. for 9 hours. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (S)-1-(3-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7-hexahydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product. The obtained crude product was dissolved in acetonitrile (227 mL), water (0.41 mL, 22.7 mmol) was added, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was concentrated at reduced pressure and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (4.01 g, 67%).

LCMS: m/z 263[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition SQD-AA05)

Third Step

(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

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(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-trifluoromethyl-furan (1.20 g, 6.29 mmol) and sodium hydride (50% by weight dispersion in mineral oil, 0.33 g, 6.86 mmol) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for 90 minutes. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (1.62 g, 63%).

LCMS: m/z 454[M+H]⁺

HPLC retention time: 1.10 minutes (analysis condition 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

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from D-proline methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 2

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(3-Fluoro- benzylidene)-amino]- pyrrolidine-2-carboxylic acid methyl ester
SQD-AA05
0.97
251

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(4aR)-1-[(3- Fluorophenyl)methyl]- 4a,5,6,7- tetrahydropyrrolo[1,2- b]pyridazine-2,4-dione
SQD-AA05
0.81
263

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(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
SQD-AA05
1.10
454

Example 3
(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 Step

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

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A 1,4-dioxane solution (4 M, 5.00 mL) of hydrogen chloride was added to (S)-4,4-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 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 at reduced pressure, and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained (S)-4,4-dimethyl-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 3

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-[(3-Fluoro- benzylidene)-amino]-4,4- dimethyl-pyrrolidine-2- carboxylic acid ethyl ester
SQD-AA05
1.09
293

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(4aS)-1-[(3- Fluorophenyl)methyl- 6,6-dimethyl-5,7- dihydro-4aH-pyrrolo[1,2- b]pyridazine-2,4-dione
SQD-AA05
0.94
291

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(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
SQD-AA05
1.15
482

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 Step

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

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(S)-5,5-Dimethyl-pyrrolidine-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 (1.00 g, 3.08 mmol) and iodomethane (0.154 mL, 2.47 mmol) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium bicarbonate solution, and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (S)-5,5-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a crude product. A 1,4-Dioxane solution (4 M, 5.00 mL) of hydrogen chloride was added to the obtained crude product, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure, and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained (S)-5,5-dimethyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 4

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-[(3-Fluoro- benzylidene)-amino]-5,5- dimethyl-pyrrolidine-2- carboxylic acid methyl ester
SQD-AA05
1.10
279

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(4aS)-1-[(3- Fluorophenyl)methyl]- 7,7-dimethyl-5,6- dihydro-4aH-pyrrolo[1,2- b]pyridazine-2,4-dione
SQD-AA05
0.93
291

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(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
SQD-AA05
1.13
482

Example 5
(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

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

TABLE 5

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-((2,3- Difluorobenzylidene)amino)- 4,4-difluoropyrrolidine-2- carboxylic acid methyl ester
SMD-TFA05
1.24
305

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(4aS)-1-[(2,3- Difluorophenyl)methyl]-6,6- difluoro-5,7-dihydro-4aH- pyrrolo[1,2-b]pyridazine-2,4- dione
SMD-TFA05
1.04
317

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(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
SMD-TFA05
1.55
508

Example 6
(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 Step

(R)-2-Methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride

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(R)-2-Methyl-pyrrolidine-2-carboxylic acid (300 mg, 2.32 mmol) was dissolved in dioxane (1.20 mL) and water (0.60 mL), and then 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. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (R)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product. In a similar manner to First Step of Example 4, the title compound was obtained from the obtained (R)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained (R)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 6

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(3-Fluoro- benzylidene)-amino]-2- methyl-pyrrolidine-2- carboxylic acid methyl ester
SQD-AA05
1.04
265

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(4aR)-1-[(3- Fluorophenyl)methyl]-4a- methyl-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazine- 2,4-dione
SQD-AA05
0.89
277

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(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
SQD-AA05
1.15
468

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 Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (R)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride obtained in First Step of Example 6 and 2,3-difluoro-benzaldehyde.

TABLE 7

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(2,3-Difluoro- benzylidene)-amino]-2- methyl-pyrrolidine-2- carboxylic acid methyl ester
SQD-AA05
1.08
283

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(4aR)-1-[(2,3- Difluorophenyl)methyl]- 4a-methyl-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazine- 2,4-dione
SQD-AA05
0.89
295

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(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
SQD-AA05
1.16
486

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[12-b]pyridazine-3-carboxamide

First Step

(S)-2-Methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride

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In a similar manner to First Step of Example 6, the title compound was obtained from (S)-2-methyl-pyrrolidine-2-carboxylic acid as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (S)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride obtained in First Step and 3-fluorobenzaldehyde.

TABLE 8

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-[(3-Fluoro- benzylidene)-amino]-2- methyl-pyrrolidine-2- carboxylic acid methyl ester
SQD-AA05
1.04
265

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(4aS)-1-[(3- Fluorophenyl)methyl]-4a- methyl-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazine- 2,4-dione
SQD-AA05
0.92
277

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(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
SQD-AA05
1.15
468

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 carrying out operations similar to those of First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (S)-2-ethyl-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluorobenzaldehyde.

TABLE 9

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-2-Ethyl-1-[(3-fluoro- benzylidene)-amino]- pyrrolidine-2-carboxylic acid ethyl ester
SQD-AA05
1.14
293

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(4aR)-4a-Ethyl-1-[(3-(- fluorophenyl)methyl]-6,7- dihydro-5H-pyrrolo[1,2- b]pyridazine-2,4-dione
SQD-AA05
0.96
291

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(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
SQD-AA05
1.22
482

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 carrying out operations similar to those of First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (R)-2-ethyl-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 2,3-difluorobenzaldehyde.

TABLE 10

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(2,3-Difluoro- benzylidene)-amino]-2- ethyl-pyrrolidine-2- carboxylic acid ethyl ester
SQD-AA05
1.08
283

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(4aR)-1-[(2,3- Difluorophenyl)methyl]- 4a-ethyl-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazine- 2,4-dione
SQD-AA05
0.89
295

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(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
SQD-AA05
1.20
500

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 carrying out operations similar to those of First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (R)-2-methyl-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 3-fluorobenzaldehyde.

TABLE 11

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(3-Fluoro- benzylidene)-amino]-2- propyl-pyrrolidine-2- carboxylic acid ethyl ester
SQD-AA05
1.16
307

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(4aR)-1-[(3- Fluorophenyl)methyl]- 4a-propyl-6,7-dihydro- 5H-pyrrolo[1,2- b]pyridazine-2,4-dione
SQD-AA05
0.99
305

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(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
SQD-AA05
1.22
496

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 carrying out operations similar to those of First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (R)-2-propyl-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride and 2,3-difluorobenzaldehyde.

TABLE 12

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(2,3-Difluoro- benzylidene)-amino]-2- propyl-pyrrolidine-2- carboxylic acid ethyl ester
SQD-AA05
1.25
325

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(4aR)-1-[(2,3- Difluorophenyl)methyl]- 4a-propyl-6,7-dihydro-5H- pyrrolo[1,2-b]pyridazine- 2,4-dione
SQD-AA05
1.03
323

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(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
SQD-AA05
1.23
514

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 Step

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

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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), potassium iodide (6.08 g, 36.6 mmol), and tripotassium phosphate (7.77 g, 36.6 mmol) were added at 25° C., and the mixture was stirred under nitrogen atmosphere at 100° C. for 2 hours. After the reaction mixture was cooled to 25° C., water (47.0 mL) was added, and the resultant was extracted with isopropyl acetate (47.0 mL). 1 N hydrochloric acid (47.0 mL) was added to the organic layer for extraction, a 5 N aqueous sodium hydroxide solution (14.1 mL) was added to the obtained aqueous solution for basification, and the mixture was extracted with isopropyl acetate (47.0 mL). The organic layer was concentrated at reduced pressure to obtain the title compound (5.15 g, 95%).

¹H-NMR (DMSO-D₆) 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 Step

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

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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 the mixture was stirred 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) was added dropwise. After the mixture was stirred at −40° C. for 2 hours, N,N-dimethylformamide (4.94 mL) was added, and the mixture was stirred for 30 minutes. After the reaction mixture was heated to −15° C., a solution of acetic acid (7.31 mL) in water (26.1 mL) and toluene (15.7 mL) were added for liquid-liquid extraction. The organic layer was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate/hexane/triethylamine) to obtain the title compound (2.90 g, 50%).

¹H-NMR (DMSO-D₆) 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 Step

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

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Methyl 1-(methylamino)cyclobutanecarboxylate paratoluenesulfonate (1.75 g, 5.54 mmol) (see Reference 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) dissolved 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 dipotassium hydrogenphosphate solution. Methanol (10.0 mL) was added to the organic layer after the 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 ammonia (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) was added at 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was concentrated, ethyl acetate and a 15% aqueous potassium dihydrogenphosphate solution were added for liquid-liquid extraction, and subsequently, the organic layer was washed with a 15% aqueous sodium hydrogen sulfite solution and a 15% aqueous dipotassium hydrogenphosphate solution. The organic layer was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate/methanol) to obtain the title compound (1.07 g, 70%).

LCMS: m/z 414[M+H]⁺

HPLC retention time: 0.65 minutes (SQD-TFA05)

Fourth Step

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

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Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-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 atmosphere for 10 minutes. 5-Ethyl-2-methylpyridine borane (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 minutes. After methanol (0.81 mL) was added to the reaction mixture at 0° C., a 5 M aqueous sodium hydroxide solution (2.44 mL) was added, and the mixture was stirred at 0° C. for 1 hour. A 25% aqueous tripotassium phosphate solution was added to the reaction mixture for liquid-liquid extraction. The organic layer was washed with a 15% aqueous sodium chloride solution, and the resultant was concentrated at reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylamino]-methylamino]cyclobutane-1-carboxylate as a crude product.

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

LCMS: m/z 791[M+H]⁺

HPLC retention time: 0.81 minutes (SQD-TFA05)

Fifth Step

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

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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 mg, 5.20 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 50° C. for 8 hours. After the reaction mixture was concentrated, 1 M hydrochloric acid (2.60 mL, 2.60 mmol) was added, and the resultant was extracted with ethyl acetate. After the organic layer was washed with a 10% aqueous potassium dihydrogenphosphate solution and a 10% aqueous sodium chloride solution, the organic layer was concentrated. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/methanol) to obtain the title compound (1.72 g, 87%).

Although tautomers of the title compound exist, isomers may be observed in some cases and not in other cases according to the type of the solvent for measurement. For example, ¹H-NMR and ¹³C-NMR of major tautomers (chloroform-D) are as follows.

LCMS: m/z 759[M+H]⁺

HPLC retention time: 0.91 minutes (SQD-TFA05)

¹H-NMR (CDCl₃) 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).

¹³C-NMR (CDCl₃) 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 (CH₂), 68.1 (CH₂), 64.1 (qC), 58.9 (CH₃), 57.4 (CH₂), 56.3 (CH₂), 43.4 (CH₃), 41.5 (CH₂), 35.0 (CH₃), 32.4 (CH₂), 24.4 (CH₂), 13.4 (CH₂).

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 Step

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

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Methyl 1-(methylamino)cyclopentanecarboxylate paratoluenesulfonate (3.60 g, 10.9 mmol) (see Reference 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) dissolved 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 dipotassium hydrogenphosphate solution. Methanol (20.0 mL) was added to the organic layer after the washing, and 12 N hydrochloric acid (7.30 mL) was added at −10° C. 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. 28% aqueous ammonia (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) was added at 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was concentrated, ethyl acetate and a 15% aqueous potassium dihydrogenphosphate solution were added for liquid-liquid extraction, and subsequently, the organic layer was washed with a 15% aqueous sodium hydrogen sulfite solution and a 15% aqueous dipotassium hydrogenphosphate solution. The organic layer was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate/methanol) to obtain the title compound (2.82 g, 90%).

LCMS: m/z 428[M+H]⁺

HPLC retention time: 0.61 minutes (SQD-FA05)

Second Step

Methyl 1-[[r[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

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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 atmosphere for 10 minutes. 5-Ethyl-2-methylpyridine borane (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. After methanol (1.00 mL) was added to the reaction mixture at 0° C., a 5 M aqueous sodium hydroxide solution (3.00 mL) was added, and the mixture was stirred at 0° C. for 1 hour. A 25% aqueous tripotassium phosphate solution was added to the reaction mixture for liquid-liquid extraction. The organic layer was washed with a 15% aqueous sodium chloride solution, and the resultant was concentrated at reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylamino]-methylamino]cyclopentane-1-carboxylate as a crude product.

The obtained 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-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (a 1.7 M ethyl acetate solution, 2.75 mL, 4.68 mmol) were added at −10° C., and the mixture was stirred under nitrogen atmosphere for 30 minutes. A 10% aqueous sodium chloride solution was added to the reaction mixture for liquid-liquid extraction. The organic layer was washed with a 15% aqueous dipotassium hydrogenphosphate solution, and the resultant was concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/methanol) to obtain the title compound (1.82 g, 97%).

LCMS: m/z 805[M+H]⁺

HPLC retention time: 0.74 minutes (SQD-FA05)

Third Step

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

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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, 1.27 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 60° C. for 8 hours. After the reaction mixture was concentrated, 1 M hydrochloric acid (1.24 mL, 1.24 mmol) was added, and the mixture was extracted with ethyl acetate. After the organic layer was washed with a 10% aqueous potassium dihydrogenphosphate solution and a 10% aqueous sodium chloride solution, the organic layer was concentrated. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/methanol) to obtain the title compound (432 mg, 90%).

LCMS: m/z 773[M+H]⁺

HPLC retention time: 0.95 minutes (SQD-FA05)

¹H-NMR (CDCl₃) 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).

¹³C-NMR (CDCl₃) 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 (CH₂), 68.0 (CH₂), 58.9 (CH₃), 57.3 (CH₂), 56.3 (CH₂), 43.3 (CH₃), 41.6 (CH₂), 37.6 (CH₂), 36.8 (CH₃), 31.4 (CH₂), 24.8 (CH₂), 23.3 (CH₂).

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 Step

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

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(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 at reduced pressure, and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained (R)-piperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 13

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(R)-1-[(3-Fluoro- benzylidene)-amino]- piperidine-2-carboxylic acid methyl ester
SQD-AA05
1.02
265

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(4aR)-1-[(3- Fluorophenyl)methyl]- 5,6,7,8-tetrahydro-4aH- pyrido[1,2-b]pyridazine- 2,4-dione
SQD-AA05
0.90
277

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(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
SQD-AA05
1.17
468

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

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from (S)-piperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 14

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-[(3-Fluoro- benzylidene)-amino]- piperidine-2-carboxylic acid methyl ester
SQD-AA05
1.03
265

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(4aS)-1-[(3- Fluorophenyl)methyl]- 5,6,7,8-tetrahydro-4aH- pyrido[1,2-b]pyridazine]- 2,4-dione
SQD-AA05
0.91
277

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(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
SQD-AA05
1.16
468

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

TABLE 15

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(S)-1-[(5,6-Difluoro-1H- indol-7-ylmethylene)- amino]-piperidine-2- carboxylic acid methyl ester
SQD-AA05
1.03
323

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(4aS)-1-[(5,6-Difluoro- 1H-indol-7-yl)methyl]- 5,6,7,8-tetrahydro-4aH- pyrido[1,2-b]pyridazine- 2,4-dione
SQD-AA05
1.00
334

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(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
SQD-AA05
1.16
525

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 Step

2-Methyl-piperidine-2-carboxylic acid methyl ester hydrochloride

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In a similar manner to First Step of Example 4, the title compound was obtained from 2-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained 2-methyl-piperidine-2-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 16

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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1-[(3-Fluoro-benzylidene)- amino]-2-methyl- piperidine-2-carboxylic acid methyl ester
SQD-AA05
1.07
279

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1-[(3- Fluorophenyl)methyl]-4a- methyl-5,6,7,8- tetrahydropyrido[1,2- b]pyridazine-2,4-dione
ZQ-01
2.53
291

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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
SQD-AA05
1.18
482

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[12-b]pyridazine-3-carboxamide

First Step

2-Ethyl-piperidine-2-carboxylic acid methyl ester hydrochloride

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In a similar manner to First Step of Example 6, the title compound was obtained from 2-ethyl-piperidine-2-carboxylic acid hydrochloride as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained 2-ethyl-piperidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluoro-benzaldehyde.

TABLE 17

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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1-{[1-(2,3-Difluoro- phenyl)-met-(Z)-ylidene]- amino}-2-ethyl- piperidine-2-carboxylic acid methyl ester
SQD-AA05
1.16
311

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1-[(2,3- Difluorophenyl)methyl]- 4a-ethyl-5,6,7,8- tetrahydropyrido[1,2- b]pyridazine-2,4-dione
SQD-AA05
1.00
323

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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
SQD-AA05
1.23
514

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 Step

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

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(1R,3 S,4S)-2-Aza-bicyclo[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 nitrogen atmosphere at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.

The organic layer was washed with water, a saturated sodium bicarbonate solution, a 10% aqueous sodium thiosulfate solution, and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester as a crude product. A solution of hydrogen chloride in 1,4-dioxane (4 M, 5.00 mL) was added to the obtained crude product, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure, and toluene was added for azeotropic removal to obtain the title compound as a crude product.

Second Step

In a similar manner to First to Third Steps of Example 1, the compounds described in the following Table were synthesized from the obtained (1 S,3 S,6R)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid methyl ester hydrochloride and 3-fluoro-benzaldehyde.

TABLE 18

Analysis
HPLC Retention

Structure
Compound name
condition
time (min)
m/z

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(1R,3S,4S)-2-[(3-Fluoro- benzylidene)-amino]-2- aza-bicyclo[2.2.1]heptane- 3-carboxylic acid methyl ester
SQD-AA05
1.02
277

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(4aS,5S,8R)-1-(3- Fluorobenzyl)tetrahydro- 1H-5,8- methanopyrido[1,2-b] pyridazine-2,4(3H,4aH)- dione
SQD-AA05
0.90
289

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(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
SQD-AA05
1.17
480

Reference Example 1-1
(4aR)-1-[(2,3-Difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid 2-methylpropyl ester

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First Step

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(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 (4.6 mL), cyano sodium borohydride (1.19 g, 18.98 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled away at reduced pressure to obtain a crude product (1.34 g, 102%) of (R)-1-((2,3-(difluorobenzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester.

Second Step

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(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) were 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) were added, and the mixture was stirred at room temperature for 30 minutes. Dichloromethane and 1 N 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 at reduced pressure. The resultant residue was purified by column chromatography on silica gel (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 minutes (analysis condition SMD-TFA05)

Third Step

(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. After the mixture was left to cool, it was concentrated at reduced pressure, 2 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-80% ethyl acetate/hexane) to obtain the title compound (25.33 g, 90%).

LCMS: m/z 395[M+H]⁺

HPLC retention time: 1.05 minutes (analysis condition SQD-FA05)

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

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Normal-pentyl aldehyde (0.959 g, 11.1 mmol) was used as a reagent, and operations similar to those of First Step of Reference Example 1-1 were carried out to obtain (R)-1-(pentylamino)-2-methylpyrrolidine-2-carboxylic acid methyl ester (1.73 g) as a crude product. The obtained hydrazine derivative was dissolved in tetrahydrofuran (14 mL), tripotassium phosphate (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 after the organic layer was washed with 1 N hydrochloric acid, water, and a brine, it was dried over magnesium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain (R)-1-(3-methoxy-3-oxo-N-pentylpropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester (1.84 g, 84%) as yellow oil. The obtained amide body (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. After the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was added, and after the organic layer was washed with 1 N hydrochloric acid, water, and a brine, it was dried over magnesium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure to obtain the title compound (1.84 g).

LCMS: m/z 297[M+H]⁺

HPLC retention time: 1.22 minutes (analysis condition SMD-TFA05)

Reference Example 2
(R)-2,5,5-Trimethylpyrrolidine-2-carboxylic methyl ester

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First Step

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4-Chlorobenzaldehyde (0.736 g, 5.23 mmol) was added to a suspension of 2-amino propanoate tert-butyl ester (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 obtained filtrate was concentrated at reduced pressure. The residue was dissolved in diethyl ether, washed with water and a brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated at reduced pressure to obtain 2-((4-chlorobenzylidene)amino)propanoate tert-butyl ester (1.29 g) as a crude product.

Second Step

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2-((4-Chlorobenzylidene)amino)propanoate tert-butyl ester (2.18 g, 12.2 mmol) obtained in 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) were 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) were added at 0° C. After the reaction mixture was stirred at 0° C. for 4 hours, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with a brine, dried over sodium sulfate, and filtered. The obtained filtrate was concentrated at reduced pressure to obtain (R)-2-((4-chlorobenzylidene)amino)-2,5-dimethylhex-4-enoic acid tert-butyl ester as a crude product.

Third Step

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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 Second Step in diethyl ether (97 mL). The reaction mixture was intensely stirred at room temperature for 4 hours. The organic layer was separated, and the aqueous layer was washed with diethyl ether. After the aqueous layer was adjusted to pH 9, it was extracted with dichloromethane. The extracts were combined, dried, and filtered, and the filtrate was concentrated at reduced pressure to obtain (R)-2-amino-2,5-dimethylhex-4-enoic acid tert-butyl ester as a crude product.

Fourth Step

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(R)-2-Amino-2,5-dimethylhex-4-enoic acid tert-butyl ester (1.03 g, 4.83 mmol) obtained in Third Step was dissolved in dichloromethane (9.7 mL), 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) were added, and the mixture was stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extracts were combined, washed with a brine, dried over sodium sulfate, and filtered, and subsequently, the filtrate was concentrated at reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain (R)-2,5-dimethyl-2-(4-methylphenylsulfonamide)hex-4-enoic acid tert-butyl ester (1.47 g, 83%) as yellow oil.

LCMS: m/z 368[M+H]⁺

HPLC retention time: 1.40 minutes (analysis condition SMD-TFA05)

Fifth Step

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(R)-2,5-Dimethyl-2-(4-methylphenylsulfonamide)hex-4-enoic acid tert-butyl ester (1.47 g, 4.00 mmol) obtained in 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. A saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extracts were combined, washed with a brine, and dried over sodium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure to obtain (R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid as a crude product.

Sixth Step

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Iodomethane (2.99 mL, 4.80 mmol) was added to a suspension of (R)-2,5,5-trimethyl-1-tosylpyrrolidine-2-carboxylic acid (1.25 g, 4.00 mmol) obtained in Fifth Step 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 hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with a brine, and dried over sodium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain (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 minutes (analysis condition SMD-TFA05)

Seventh Step

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

¹H-NMR (CDCl₃) 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).

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

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First Step

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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 a solution of 2,3-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 celite pad, and the filtrate was concentrated at reduced pressure. The residue was dissolved in ethyl acetate, washed with water, a 2 N aqueous sodium hydroxide solution, water, and a brine, and the organic layer was dried over sodium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain 4-(2-(2,3-difluorophenoxy)ethyl)morpholine (5.60 g, 99%) as colorless oil.

LCMS: m/z 244[M+H]⁺

HPLC retention time: 0.68 minutes (analysis condition SMD-TFA05)

Second Step

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 the mixture was stirred 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 ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the extracts were combined and washed with a brine, dried over sodium sulfate, and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (758 mg, 68%) as yellow oil.

LCMS: m/z 272[M+H]⁺

HPLC retention time: 0.62 minutes (analysis condition SMD-TFA05)

Reference Example 4
(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 2-methylpropyl ester

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First Step

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2,3-Difluoro-4-(2-morpholinoethoxy)benzaldehyde and methyl (R)-2-methyl-pyrrolidine-2-carboxylic acid hydrochloride were used, and operations similar to those of First to Third Steps of Example 1 were carried out to synthesize 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 minutes (analysis condition SMD-TFA05)

Second Step

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(R)-1-((2,3-Difluoro-4-(2-morpholinoethoxy)benzylidene)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester was used, and operations similar to those of First Step of Reference Example 1-1 were carried out to obtain (R)-1-((2,3-difluoro-4-(2-morpholinoethoxy)benzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester as a crude product.

LCMS: m/z 414[M+H]⁺

HPLC retention time: 0.63 minutes (analysis condition SMD-TFA05)

Third Step

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(R)-1-((2,3-Difluoro-4-(2-morpholinoethoxy)benzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester and 3-butyloxy-3-propionic acid were used, and operations similar to those of Reference Example 1-2 were carried out to synthesize (R)-1-(N-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester.

LCMS: m/z 556[M+H]⁺

HPLC retention time: 1.03 minutes (analysis condition SMD-TFA05)

Fourth Step

(R)-1-(N-(2,3-Difluoro-4-(2-morpholinoethoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylic acid methyl ester was used, and operations similar to those of Reference Example 1-2 were carried out to synthesize the title compound.

LCMS: m/z 524[M+H]⁺

HPLC retention time: 1.04 minutes (analysis condition SMD-TFA05)

The ester intermediates described in the following Table were synthesized using the corresponding aldehyde reagents and proline derivatives to carry out operations similar to those of Reference Example 1-1 or Reference Example 1-2.

TABLE 19

Reference

LCMS
Retention
Ester

Example

analysis
time
intermediate

No.
Ester
condition No.
(min)
m/z

5

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SQD-FA05
1.12
521 [M + H]⁺

6

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SQD-FA05
0.62
524 [M + H]⁺

7

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SMD-TFA50
0.47
335 [M + H]⁺

8

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SMD-TFA05
1.08
342 [M + H]⁺

9

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SMD-TFA50
0.88
413 [M + H]⁺

10

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SQD-FA05
0.82
362 [M + H]⁺

11

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SQD-FA05
1.12
423 [M + H]⁺

12

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SMD-TFA05
1.14
377 [M + H]⁺

Reference Example 13
4-(Trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]aniline

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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 nitrogen atmosphere, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was concentrated at 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 at reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether) to obtain the title compound (63 g, 98%).

LCMS: m/z 307[M+H]⁺

HPLC retention time: 0.99 minutes (analysis condition SQD-AA05)

Reference Example 14
2-Iodo-5-(2-methoxyethoxy)-4-(trifluoromethyl)aniline

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First Step

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

HPLC retention time: 0.63 minutes (analysis condition SQD-AA50)

TLC (silica gel plate) Rf value: 0.37 (10% ethyl acetate/hexane)

Second Step

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4-Bromo-2-(2-methoxyethoxy)-1-(trifluoromethyl)benzene (231.2 mg, 0.773 mmol), carbamic acid t-butyl (109 mg, 0.928 mmol), palladium acetate (II) (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) were 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 potassium dihydrogenphosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-20% ethyl acetate/hexane) to obtain (3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)carbamic acid tert-butyl (192.5 mg, 74%).

LCMS: m/z 334[M−H]⁻

HPLC retention time: 1.02 minutes (analysis condition SQD-AA05)

Third Step

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A solution of 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 at reduced pressure, ether/hexane (1/3) was added to the resultant residue, the deposited solid was collected by filtration, and the resultant was dried under vacuum to obtain 3-(2-methoxyethoxy)-4-(trifluoromethyl)aniline hydrochloride (128.1 mg, 82%).

LCMS: m/z 236[M+H]⁺

HPLC retention time: 0.83 minutes (analysis condition SQD-AA05)

Fourth Step

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 at reduced pressure, ethyl acetate was added, washed with 0.5 N sodium hydroxide and a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-40% ethyl acetate/hexane) to obtain the title compound (69.2 mg, 93%).

LCMS: m/z 362[M+H]⁺

HPLC retention time: 1.19 minutes (analysis condition SMD-TFA05)

Reference Example 15
2′,3′-Dimethoxy-4-(2-methoxyethoxy)-5-(trifluoromethyl)-[1,1′-biphenyl]-2-amine

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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)ferrocene dichloropalladium (II) (7.9 mg, 0.0096 mmol), then a 2M aqueous potassium carbonate solution (0.38 mL) was added, and the mixture was stirred under nitrogen atmosphere at 100° C. for 1 hour. A 0.37 M aqueous potassium dihydrogenphosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-40% ethyl acetate/hexane), to obtain the title compound (41.1 mg, 58%).

LCMS: m/z 372[M+H]⁺

HPLC retention time: 1.21 minutes (analysis condition SMD-TFA05)

The boronic acid derivatives and halides described in the following Table were used, and operations similar to those of Reference Example 13 or Reference Example 15 were carried out to synthesize aniline intermediates described in the following Table.

TABLE 20

Reference

Aniline

Example

Boronic acid

intermediate

No.
Aniline
derivative
Halide
m/z

16

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298 [M + H]⁺

17

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281 [M + H]⁺

18

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359 [M + H]⁺

19

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281 [M + H]⁺

20

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326 [M + H]⁺

21

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312 [M + H]⁺

22

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372 [M + H]⁺

23

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351 [M + H]⁺

24

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323 [M + H]⁺

25

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323 [M + H]⁺

26

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346 [M + H]⁺

27

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264 [M + H]⁺

28

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267 [M − H]⁻

29

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285 [M + H]⁺

30

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273 [M + H]⁺

31

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274 [M + H]⁺

32

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264 [M + H]⁺

33

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298 [M + H]⁺

34

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283 [M + H]⁺

35

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307 [M + H]⁺

36

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269 [M + H]⁺

37

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385 [M + H]⁺

38

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307 [M − H]⁻

39

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264 [M + H]⁺

40

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294 [M + H]⁺

41

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307 [M + H]⁺

42

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307 [M + H]⁺

43

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278 [M + H]⁺

44

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308 [M + H]⁺

45

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286 [M + H]⁺

46

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308 [M + H]⁺

47

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289 [M + H]⁺

48

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287 [M + H]⁺

49

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264 [M + H]⁺

50

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308 [M + H]⁺

51

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308 [M + H]⁺

52

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288 [M + H]⁺

53

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274 [M + H]⁺

54

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304 [M + H]⁺

55

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332 [M + H]⁺

56

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286 [M + H]⁺

57

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300 [M + H]⁺

58

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274 [M + H]⁺

59

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263 [M − H]⁻

60

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287 [M + H]⁺

61

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274 [M + H]⁺

62

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319 [M + H]⁺

Reference Example 63
6-(2-Amino-5-(trifluoromethyl)phenyl)pyrimidine-4-carbonitrile

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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) were dissolved in dimethylsulfoxide (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 potassium dihydrogenphosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by C18 reverse-phase column chromatography (40-100% acetonitrile/water) to obtain the title compound (365.6 mg, 38%).

LCMS: m/z 265[M+H]⁺

HPLC retention time: 1.16 minutes (analysis condition SMD-TFA05)

Reference Example 64
5-(2-Amino-5-(trifluoromethyl)phenyl)-4-methoxypyrimidine-2-carbonitrile

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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) was heated and stirred under nitrogen atmosphere at 80° C. for 1 hour. Further, the reaction mixture was heated and stirred at 110° C. for 9 hours. The reaction mixture was purified by C18 reverse-phase column chromatography (acetonitrile-water, 0.03% formic acid) to obtain 5-(2-amino-5-(trifluoromethyl)phenyl)-4-methoxypyrimidine-2-carbonitrile (57 mg, 66%).

LCMS: m/z 295[M+H]⁺

HPLC retention time: 0.82 minutes (analysis condition SQD-FA05)

Reference Example 65
6-(2-Amino-5-(trifluoromethyl)phenyl)-5-chloropyrimidine-4-carbonitrile

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2-(5,6-Dichloropyrimidin-4-yl)-4-(trifluoromethyl)aniline was used, and operations similar to those of Reference Example 63 were carried out to synthesize the title compound.

LCMS: m/z 299[M+H]⁺

HPLC retention time: 0.82 minutes (analysis condition SQD-FA05)

Reference Example 66
6-(2-Amino-5-(trifluoromethyl)phenyl)-5-methoxypyrimidine-4-carbonitrile

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2-(6-Chloro-5-methoxypyrimidin-4-yl)-4-(trifluoromethyl)aniline was used, and operations similar to those of Reference Example 63 were carried out to synthesize the title compound.

LCMS: m/z 295[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition SQD-FA05)

Reference Example 67
6-(2-Amino-5-(trifluoromethyl)phenyl)-5-methylpyrimidine-4-carbonitrile

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2-(6-Chloro-5-methylpyrimidin-4-yl)-4-(trifluoromethyl)aniline was used, and operations similar to those of Reference Example 63 were carried out to synthesize the title compound.

LCMS: m/z 279[M+H]⁺

HPLC retention time: 0.78 minutes (analysis condition SQD-FA05)

Reference Example 68
5-(2-Amino-5-(trifluoromethyl)phenyl)pyrazine-2-carbonitrile

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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 atmosphere at 80° C. for 18 hours. The reaction mixture was purified by 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 minutes (analysis condition SQD-FA05)

Reference Example 69
2-(6-Methylpyrimidin-4-yl)-4-(trifluoromethyl)aniline

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2-(6-Chloropyrimidin-4-yl)-4-(trifluoromethyl)aniline (51.9 mg, 0.19 mmol), trimethyl boroxine (0.053 mL, 0.379 mmol), bis(triphenylphosphine)palladium (II) chloride (13.3 mg, 0.019 mmol), and tripotassium phosphate (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. A 0.37 M aqueous potassium dihydrogenphosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-30% ethyl acetate/hexane) to obtain the title compound (27.4 mg, 57%).

LCMS: m/z 254[M+H]⁺

HPLC retention time: 0.93 minutes (analysis condition SQD-AA05)

Reference Example 70
2-(Trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine

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First Step

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4-Iodo-2-(trifluoromethyl)pyrimidine-5-carboxylic acid ethyl ester and (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used, and operations similar to those of Reference Example 13 were carried out to synthesize 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid ethyl ester.

LCMS: m/z 366[M+H]⁺

HPLC retention time: 1.26 minutes (analysis condition SMD-TFA05)

Second Step

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2-(Trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid ethyl ester obtained in First Step (36 mg, 0.10 mmol) was dissolved in a mixture solution of ethanol (1 mL) and water (1 mL), and sodium hydroxide (7.9 mg, 0.20 mmol) was added at room temperature. After the mixture was stirred at room temperature for 1 hour, the solvent was concentrated at reduced pressure, and 1 N hydrochloric acid (5 mL) was added to the residue. After the resultant was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated at reduced pressure to obtain 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 minutes (analysis condition SMD-TFA05)

Third Step

N,N-dimethylformamide (1.5 mL) was added to 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5-carboxylic acid obtained in 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) was added to the reaction mixture, and the resultant was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, a 1 N aqueous sodium hydroxide solution was added, and after the resultant was extracted with ethyl acetate, it was dried over magnesium sulfate and filtered. The filtrate was concentrated at reduced pressure to obtain the title compound (26 mg) as a crude product.

LCMS: m/z 309[M+H]⁺

HPLC retention time: 1.08 minutes (analysis condition SMD-TFA05)

Reference Example 71
4-Bromo-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

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2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 4-chloro-6-(trifluoromethyl)pyrimidine were used as a reagent and a starting material, respectively, and operations similar to those of Reference Example 13 were carried out to obtain 2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline. 1-Bromopyrrolidine-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 to 55° C. and stirred for 3.5 hours. The reaction mixture was cooled to room temperature, and azeotropic removal with toluene was carried out three times. The residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (60 mg, 50%) as a yellow solid.

LCMS: m/z 318[M+H]⁺

HPLC retention time: 1.24 minutes (analysis condition SMD-TFA05)

Example 21
(4aR)-1-[(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

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(4aR)-1-[(2,3-Difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylic acid 2-methylpropyl ester (20 mg, 0.0567 mmol) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Reference 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. After the mixture was left to cool, the resultant was concentrated at reduced pressure, and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (36 mg, 99%).

LCMS: m/z 628[M+H]⁺

HPLC retention time: 1.17 minutes (analysis condition SQD-AA05)

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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 Reference Example 13 and 15 to 71 and the appropriate ester intermediates of Reference Examples 1-1 and 1-2 and Reference Examples 4 to 12 were used, and operations similar to those of Example 21 were carried out to synthesize the compounds described in the following Table. Note that in Examples 59 and 60, N,N-dimethylformamide was used as a solvent instead of toluene.

TABLE 21

LCMS
Retention

Example

analysis
time
m/z

No.
Structural formula
condition No.
(min)
[M + H]⁺

22

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QC-SMD- TFA05
1.26
728

23

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QC-SMD- TFA05
1.65
619

24

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QC-SMD- TFA05
1.63
599

25

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QC-SMD- TFA05
1.61
615

26

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QC-SMD- TFA05
1.75
571

27

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QC-SMD- TFA05
1.63
519

28

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SQD-AA05
1.18
510

29

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SQD-AA05
1.16
528

30

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SQD-AA05
1.17
560

31

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SQD-AA05
1.22
526

32

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QC-SMD- TFA05
1.64
528

33

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SQD-AA05
1.17
588

34

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SQD-AA05
1.17
610

35

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SQD-AA05
1.19
492

36

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SQD-AA05
1.16
510

37

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QC-SMD- TFA05
1.74
570

38

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QC-SMD- TFA05
1.72
526

39

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QC-SMD- TFA05
1.76
567

40

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SQD-AA05
1.11
577

41

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QC-SMD- TFA05
1.8
586

42

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QC-SMD- TFA05
1.77
620

43

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QC-SMD- TFA05
1.71
526

44

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SQD-AA05
1.22
618

45

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SQD-AA05
1.16
584

46

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SQD-AA05
1.17
601

47

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QC-SMD- TFA05
1.71
607

48

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QC-SMD- TFA05
1.61
601

49

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QC-SMD- TFA05
1.64
624

50

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QC-SMD- TFA05
1.68
679

51

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QC-SMD- TFA05
1.59
607

52

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QC-SMD- TFA05
1.25
713

53

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QC-SMD- TFA05
1.29
748

54

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QC-SMD- TFA05
1.62
607

55

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QC-SMD- TFA05
1.29
744

56

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QC-SMD- TFA05
1.64
615

57

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QC-SMD- TFA05
1.62
585

58

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QC-SMD- TFA05
1.65
552

59

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QC-SMD- TFA05
1.3
772

60

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QC-SMD- TFA05
1.35
772

61

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QC-SMD- TFA05
1.73
655

62

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QC-SMD- TFA05
1.72
634

63

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QC-SMD- TFA05
1.73
655

64

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QC-SMD- TFA05
1.65
638

65

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QC-SMD- TFA05
1.67
646

66

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QC-SMD- TFA05
1.73
632

67

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QC-SMD- TFA05
1.61
594

68

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SQD-AA05
1.14
618

69

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QC-SMD- TFA05
1.68
608

70

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QC-SMD- TFA05
1.70
628

71

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QC-SMD- TFA05
1.69
671

72

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QC-SMD- TFA05
1.65
620

73

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QC-SMD- TFA05
1.72
638

74

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QC-SMD- TFA05
1.71
594

75

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SQD-AA05
1.20
510

76

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SQD-AA05
1.19
466

77

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SQD-AA05
1.24
492

78

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SQD-AA05
1.11
493

79

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SQD-AA05
1.10
449

80

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QC-SMD- TFA05
1.67
603

81

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QC-SMD- TFA05
1.40
589

82

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QC-SMD- TFA05
1.58
584

83

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SQD-AA05
1.19
609

84

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SQD-AA05
1.19
627

85

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QC-SMD- TFA05
1.70
705

86

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QC-SMD- TFA05
1.66
593

87

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QC-SMD- TFA05
1.60
666

88

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SQD-AA05
1.16
540

89

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SQD-AA05
1.19
482

90

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SQD-AA05
1.17
627

91

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SMD-AA05
1.71
627

92

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QC-SMD- TFA05
1.66
692

93

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QC-SMD- TFA05
1.72
589

94

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QC-SMD- TFA05
1.59
584

95

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QC-SMD- TFA05
1.60
585

96

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QC-SMD- TFA05
1.68
606

97

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QC-SMD- TFA05
1.71
605

98

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QC-SMD- TFA05
1.65
652

99

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QC-SMD- TFA05
1.60
629

100

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QC-SMD- TFA05
1.64
585

101

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QC-SMD- TFA05
1.65
598

102

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QC-SMD- TFA05
1.29
722

103

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QC-SMD- TFA05
1.30
734

104

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QC-SMD- TFA05
1.28
735

105

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QC-SMD- TFA05
1.64
606

106

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QC-SMD- TFA05
1.25
757

107

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SMD-TFA05
1.27
723

108

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QC-SMD- TFA05
1.30
757

Although tautomers of for the compounds described in this table exist, for example, ¹H-NMR of Examples 22 and 52 is as follows.

Example 22

Major Tautomer

¹H-NMR (CDCl₃) 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 (2H, t, J=5.7 Hz), 3.74 (4H, t, J=4.5 Hz), 3.29 (1H, 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

¹H-NMR (CDCl₃) 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 (3H, s), 1.67-1.62 (2H, m), 1.44-1.41 (1H, m), 0.79 (3H, s).

Example 52

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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

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(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 a starting material, and operations similar to those of Reference Example 69 were carried out to obtain the title compound.

LCMS: m/z 598[M+H]⁺

HPLC retention time: 1.63 minutes (analysis condition 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

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First Step

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2-Bromo-4-(trifluoromethyl)aniline and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid were used as a reagent and a starting material, respectively, and operations similar to those of Reference Example 13 were carried out to obtain 4-(2-amino-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl.

LCMS: m/z 243[M+H—C₄H₉OCO]⁺

HPLC retention time: 1.31 minutes (analysis condition SMD-TFA05)

Second Step

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

Third Step

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The aniline derivative obtained in Second Step and the compound described in Reference Example 1-1 were used as a reagent and a starting material, respectively, and operations similar to those of Example 21 were carried out to obtain 4-[2-[[(4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carbonyl]amino]-5-(trifluoromethyl)phenyl]piperidine-1-carboxylic acid tert-butyl.

LCMS: m/z 565[M+H—C₄H₉OCO]⁺

HPLC retention time: 1.78 minutes (analysis condition SMD-TFA05)

Fourth Step

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A 4 N hydrogen chloride/dioxane solution (5 mL) was added to the amide derivative obtained in Third Step (0.81 g, 1.23 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure to obtain (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 minutes (analysis condition SMD-TFA05)

Fifth Step

The hydrochloride obtained in 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, 0.050 mmol) were added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was purified directly by 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 minutes (analysis condition 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

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(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 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. A 0.37 M aqueous potassium dihydrogenphosphate solution and dichloromethane were added to the reaction mixture, the mixture was intensely stirred, and subsequently, the water layer was separated by a phase separator, and the organic layer was concentrated at reduced pressure. The resultant residue was purified by C18 reverse-phase column chromatography (30-95% acetonitrile/water) to obtain the title compound (19.7 mg, 89%).

LCMS: m/z 681[M+H]⁺

HPLC retention time: 0.99 minutes (analysis condition SMD-TFA50)

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]pyridazine-3-carbonyl]amino]-5-(trifluoromethyl)phenyl]-3-cyanopyridin-2-yl]-methylamino]acetate

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N-Methylglycine methyl ester was used as a reagent, and operations similar to those of Example 111 were carried out to synthesize the title compound.

LCMS: m/z 685[M+H]⁺

HPLC retention time: 1.65 minutes (analysis condition 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

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(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 potassium dihydrogenphosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by C18 reverse-phase column chromatography (30-90% acetonitrile (0.1% formic acid)/water (0.1% formic acid) to obtain the title compound (17.7 mg, 49%).

LCMS: m/z 630[M+H]⁺

HPLC retention time: 1.04 minutes (analysis condition SMD-TFA50)

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

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Sodium methoxide was used as a reagent, and operations similar to those of Example 113 were carried out to synthesize the title compound.

LCMS: m/z 614[M+H]⁺

HPLC retention time: 1.62 minutes (analysis condition QC-SMD-TFA05)

Reference Example 72
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-ynoate

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A suspension of (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 2-methylpropyl ester (Reference Example 5) (250 mg, 0.480 mmol), hept-6-ynoic acid (0.182 mL, 1.44 mmol), copper (I) 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) was stirred under nitrogen atmosphere at room temperature for 2.5 hours. At the same time, the completely same reaction was run in another vessel on the same scale, and both resultants were combined and purified by C18 reverse-phase column chromatography to obtain the title compound (328 mg, 66%) as yellow oil.

LCMS: m/z 519[M+H]⁺

HPLC retention time: 1.00 minute (analysis condition SQD-FA05)

Reference Example 73
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

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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-ynoic acid (Reference Example 72) (358 mg, 0.69 mmol) and palladium hydroxide-carbon (20 wt. %, about 50% wet with water, 145 mg) in 2,2,2-trifluoroethanol (7 mL) was stirred under hydrogen atmosphere at room temperature for 2 hours. Further, palladium hydroxide-carbon (20 wt. %, about 50% wet with water, 145 mg) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction mixture was filtered through a celite pad, the filtrate was concentrated to obtain the title compound (361 mg, 100%) as light brown oil.

LCMS: m/z 523[M+H]⁺

HPLC retention time: 1.05 minutes (analysis condition SQD-AA05)

Example 115
7-[4-[[(4aR)-4-Hydroxy-4a-methyl-3-[[2-(6-methylsulfanylpyridin-3-v1)-4-(trifluoromethyl)phenyl]carbamoyl]-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazin-1-yl]methyl]-2,3-difluorophenyl]heptanoate

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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 (Reference Example 73) and 2-(6-(methylthio)pyridin-3-yl)-4-(trifluoromethyl)aniline were used, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 733[M+H]⁺

HPLC retention time: 1.25 minutes (analysis condition 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

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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 (Reference Example 73) and 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)aniline were used, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 721[M+H]⁺

HPLC retention time: 1.22 minutes (analysis condition 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-ynoate

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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-ynoic acid (Reference Example 72) was used as a starting material, 2-(6-(methylthio)pyridin-3-yl)-4-(trifluoromethyl)aniline was used as a reagent, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 729[M+H]⁺

HPLC retention time: 1.61 minutes (analysis condition 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-ynoate

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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-ynoic acid (Reference Example 72) and 2-(2-(methylthio)pyrimidin-5-yl)-4-(trifluoromethyl)aniline were used, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 730[M+H]⁺

HPLC retention time: 1.58 minutes (analysis condition 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-ynoate

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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-ynoic acid (Reference Example 72) and 4-(trifluoromethyl)-2-(5-(trifluoromethyl)pyridin-3-yl)aniline were used, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 751[M+H]⁺

HPLC retention time: 1.60 minutes (analysis condition SMD-TFA05)

Reference Example 74
(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 2-methylpropyl ester

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First Step

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4-(Benzyloxy)-2,3-difluorobenzaldehyde and (R)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride were used as a reagent and a starting material, respectively, and operations similar to those of First Step of Example 1 and Reference Example 1-1 were carried out to synthesize (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 2-methylpropyl ester.

Second Step

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Palladium-carbon (10 wt. %, 120 mg) was added to a solution of (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 2-methylpropyl ester (1.56 g, 3.12 mmol) in ethyl acetate (100 mL), and the mixture was stirred under hydrogen atmosphere at room temperature for 30 minutes. The reaction mixture was filtered through celite, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol) to obtain (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 2-methylpropyl ester (1.02 g, 80%).

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 1.24 minutes (analysis condition SMD-TFA05)

Third Step

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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 hydrogensulfate (257 mg, 0.757 mmol) was added to this mixture, and the resultant was intensely stirred at room temperature overnight. After water was added, the layer was extracted with hexane/diethyl ether (1:4) four times, and the organic layers were combined and dried over magnesium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain (S)-4-((4-bromobutoxy)methyl)-2,2-dimethyl-1,3-dioxolane (2.54 g, 63%) as colorless oil.

Fourth Step

Cesium carbonate (1.20 mg, 3.65 mmol) was added to a solution of (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 2-methylpropyl ester (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. After the mixture was cooled to room temperature, a 0.37 M aqueous potassium dihydrogenphosphate solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a brine, and dried over magnesium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol) to obtain the title compound (414 mg, 57%).

LCMS: m/z 597[M+H]⁺

HPLC retention time: 1.52 minutes (analysis condition 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-v1)-4-(trifluoromethyl)phenyl]-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

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(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 2-methylpropyl ester (Reference 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 at reduced pressure, the resultant 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 hour and a half. Water was added to the reaction mixture, and the resultant white turbid solution was purified by 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 minutes (analysis condition 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

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LCMS: m/z 755[M+H]⁺

HPLC retention time: 1.50 minutes (analysis condition 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

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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. The insolubles were filtered, and the filtrate was purified directly by 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 minutes (analysis condition SQD-FA05)

Reference Example 75
((4S,5S)-5-((Hept-6-yn-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol

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

Reference Example 76
(R)-4-((3-Bromopropoxy)methyl)-2,2-dimethyl-1,3-dioxolane

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(R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (615 mg, 4.66 mmol) 6-bromo-1-hexyne (500 mg, 3.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (60 wt. %, a mineral oil dispersion, 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. After the organic layer was washed with a brine and dried over sodium sulfate, the resultant was concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel to obtain (R)-4-((hex-5-yn-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolane (390 mg, 59%) as clear liquid.

¹H-NMR (CDCl₃) 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).

Reference Example 77
4-(Prop-2-yn-1-yl)morpholin-3-one

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Sodium hydride (60 wt. %, a mineral oil dispersion, 187 mg, 4.68 mmol) was added to a solution of morpholin-3-one (430 mg, 4.25 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was 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 after the reaction mixture was washed serially with a saturated aqueous ammonium chloride solution, water, and a brine and dried over magnesium sulfate, the resultant was concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel to obtain the title compound (312 mg, 53%) as clear oil.

¹H-NMR (CDCl₃) 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-ynil]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

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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 a solution of (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) (30 mg, 0.040 mmol), bis(triphenylphosphine)palladium (II) chloride (2.83 mg, 0.0404 mmol), and copper (I) iodide (1.54 mg, 0.0081 mmol) in N,N-dimethylformamide (0.40 mL) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 14 hours. Formic acid was added to the reaction mixture, and the mixture was purified directly 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 minutes (analysis condition QC-SMD-TFA05)

Example 124
(4aR)-1-[[2,6-Difluoro-4-[7-[(2S,3S)-2,3,4-trihydroxybutoxy]hept-1-ynil]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

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((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) were added to a 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) under nitrogen atmosphere at 0° C. 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 purified directly by C18 reverse-phase column chromatography to obtain the title compound (32 mg, 82%) as an orange amorphous solid.

LCMS: m/z 841[M+H]⁺

HPLC retention time: 0.90 minutes (analysis condition 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

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A suspension of (4aR)-1-[[2,6-difluoro-4-[7-[(2S,3S)-2,3,4-trihydroxybutoxy]hept-1-ynil]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-carbon (20 wt. %, 3.34 mg, 0.00476 mmol) in ethyl acetate was stirred under hydrogen atmosphere at room temperature for 10 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated at reduced pressure. The residue was purified by C18 reverse-phase column chromatography to obtain the title compound (11.5 mg, 57%) as a colorless amorphous solid.

LCMS: m/z 845[M+H]⁺

HPLC retention time: 1.60 minutes (analysis condition 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]pyridazine-3-carboxamide

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Triisopropylsilyl acetylene was used as a reagent, and operations similar to those of First Step of Example 123 were carried out 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 obtained crude product was dissolved in tetrahydrofuran (0.15 mL), a 1 M tetrahydrofuran solution (0.12 mL) of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (0.5 mL), water (0.5 mL), and dimethylsulfoxide (1 mL) were added to the reaction mixture, and the mixture was purified by C18 reverse-phase column chromatography to obtain the title compound (22 mg, 84%) as a white amorphous solid.

LCMS: m/z 652[M+H]⁺

HPLC retention time: 0.87 minutes (analysis condition SQD-FA50).

The appropriate iodide derivatives of Examples 319-323 and appropriate terminal alkyne reagents were used, and operations similar to those of Example 123 were carried out to synthesize the compounds described in the following Table.

TABLE 22

Ex-

LCMS
Reten-

am-

analysis
tion
m/z

ple

condition
time
[M +

No.
Structural formula
No.
(min)
H]⁺

127

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SQD-AA05
1.18
730

128

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QC-SMD- TFA05
1.60
753

129

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QC-SMD- TFA05
1.62
738

130

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QC-SMD- TFA05
1.69
735

131

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SQD-AA05
1.14
631

132

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QC-SMD- TFA05
1.33
750

133

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QC-SMD- TFA05
1.56
648

134

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QC-SMD- TFA05
1.60
686

135

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QC-SMD- TFA05
1.65
714

136

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QC-SMD- TFA05
1.57
804

137

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QC-SMD- TFA05
1.58
716

138

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QC-SMD- TFA05
1.62
700

139

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QC-SMD- TFA05
1.57
760

140

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QC-SMD- TFA05
1.34
750

Although tautomers of some of the compounds described in this table exist, isomers may be observed in some cases and not in other cases according to the type of the solvent for measurement. For example, ¹H-NMR of Example 129 (dimethylsulfoxide-D6) and Example 140 (chloroform-D) is as follows.

Example 129

¹H-NMR (DMSO-D₆) 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

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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 to 323 and appropriate terminal alkyne reagents were used, and operations similar to those of Example 123 and Example 125 were carried out to synthesize the compounds described in the following Table.

TABLE 23

Ex-

LCMS
Reten-

am-

analysis
tion
m/z

ple

condition
time
[M +

No.
Structural formula
No.
(min)
H]⁺

141

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QC-SMD- TFA05
1.61
743

142

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QC-SMD- TFA05
1.59
808

The appropriate iodide derivatives of Examples 319 to 323 and appropriate terminal alkyne reagents including that in Reference Example 76 were used, and operations similar to those of Example 124 were carried out to synthesize the compounds described in the following Table.

TABLE 24

Ex-

LCMS

am-

analysis
Retention
m/z

ple

condition
time
[M +

No.
Structural formula
No.
(min)
H]⁺

143

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QC-SMD- TFA05
1.56
797

144

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QC-SMD- TFA05
1.58
797

145

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QC-SMD- TFA05
1.51
769

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]pyridazine-3-carboxamide hydrochloride

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(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]pyridazine-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, 0.20 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 60° C. for 3 hours. Dimethylsulfoxide (0.4 mL) and concentrated hydrochloric acid (0.1 mL) were added to the reaction mixture at 0° C., and after the mixture was stirred for 5 minutes, the resultant was purified directly by C-18 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 minutes (analysis condition 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]pyridazine-3-carboxamide

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First Step

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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 hydrogensulfate tetra n-butylammonium (0.19 g, 0.57 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. Water (30 mL) was added to the reaction mixture, and after the resultant was extracted with diethyl ether, the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain (S)-4-((3-bromopropoxy)methyl)-2,2-dimethyl-1,3-dioxolane (640 mg, 22%) as clear liquid.

Second Step

(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]pyridazine-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) were dissolved in N,N-dimethylformamide (3 mL), cesium carbonate (0.86 g, 6.23 mmol) was added, 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 the insolubles were filtered and concentrated at reduced pressure. After methanol (10 mL) was added to the resultant 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 blown with nitrogen for 1 hour to remove an excessive amount of hydrogen chloride, and subsequently, dimethylsulfoxide (5 mL) was added, methanol was removed at reduced pressure, and the resultant residue was purified by C-18 reverse-phase column chromatography on silica gel (water/acetonitrile) to obtain the title compound (1.2 g, 95%) as a white amorphous solid.

LCMS: m/z 775[M+H]⁺

HPLC retention time: 1.49 minutes (analysis condition SMD-TFA05)

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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).

Reference Example 78
(S)-4-(((5-Bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane

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1,5-Dibromopentane and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol were used, and operations similar to those of First Step of Example 147 were carried out to obtain (S)-4-((hex-5-yn-1-yloxy)methyl)-2,2-dimethyl-1,3-dioxolane as clear liquid.

¹H-NMR (CDCl₃) 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).

Reference Example 79
(R)-4-(((5-Bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane

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1,5-Dibromopentane and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol were used, and operations similar to those of First Step of Example 147 were carried out 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]pyridazine-3-carboxamide hydrochloride

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(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]pyridazine-3-carboxamide (Example 329) and 4-(2-chloroethyl)morpholine hydrochloride were used, and operations similar to those of Example 146 were carried out to synthesize the title compound.

LCMS: m/z 789[M+H]⁺

HPLC retention time: 1.29 minutes (analysis condition 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]pyridazine-3-carboxamide

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First Step

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4-(Benzyloxy)-3-chlorobenzaldehyde and (R)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride were used, and operations similar to those of Reference Example 4 were carried out to synthesize (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 2-methylpropyl ester.

Second Step

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(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 2-methylpropyl ester was used, and operations similar to those of Second Step of Reference Example 74 were carried out to synthesize (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 2-methylpropyl ester.

Third Step

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(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 2-methylpropyl ester and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Reference Example 13) were used, and operations similar to those of Example 21 were carried out 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 Step

(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 and 4-(2-chloroethyl)morpholine hydrochloride were used, and operations similar to those of Example 146 were carried out to synthesize the title compound.

LCMS: m/z 754[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition 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

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First Step

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(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]pyridazine-3-carboxamide (Example 324) and bromoacetic acid tert-butyl ester were used, and operations similar to those of Example 146 were carried out to synthesize 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 tert-butyl ester.

LCMS: m/z 757[M+H]⁺

HPLC retention time: 1.23 minutes (analysis condition SQD-FA05)

Second Step

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Trifluoroacetic acid (0.3 mL, 4 mmol) was added to a 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 tert-butyl ester (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 at reduced pressure, and the resultant residue was purified by 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 minutes (analysis condition SQD-FA05)

Third Step

(Diazomethyl)trimethylsilane (0.0125 mL, 0.025 mmol) was added to a 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. After formic acid (0.005 mL) was added to the reaction mixture, the resultant was concentrated at reduced pressure, and the resultant 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 minutes (analysis condition 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

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(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 were used, and operations similar to those of Example 146 were carried out to synthesize the title compound.

LCMS: m/z 725[M+H]⁺

HPLC retention time: 1.37 minutes (analysis condition QC-SMD-TFA05)

The phenolic derivatives of Examples 326, 327, and 330 and alkyl bromide reagents including those in Reference Examples 78 and 79 were used, and operations similar to those of Second Step of Example 147 were carried out to synthesize the compounds of the Examples described in the following Table.

TABLE 25

Ex-

Reten-

am-

LCMS
tion
m/z

ple

analysis
time
[M +

No.
Structural formula
condition No.
(min)
H]⁺

152

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QC-SMD- TFA05
1.53
790

153

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QC-SMD- TFA05
1.56
803

154

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QC-SMD- TFA05
1.60
817

155

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QC-SMD- TFA05
1.60
817

156

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QC-SMD- TFA05
1.49
819

Although tautomers of some of the compounds described in this table exist, isomers may be observed in some cases and not in other cases according to the type of the solvent for measurement. For example, ¹H-NMR of Example 152 (chloroform-D) and Example 156 (dimethylsulfoxide-D6) is as follows.

Example 152

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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

¹H-NMR (DMSO-D₆) 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-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

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Triphenylphosphine (17.2 mg, 0.066 mmol), N-(2-hydroxy ethyl)morpholine (7.5 mg, 0.057 mmol), and diethyl azodicarboxylate (0.03 mL, 0.065 mmol) were added to a solution of (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 for 1.5 hours. After the reaction mixture was concentrated, the residue was purified by reverse-phase column chromatography on silica gel to obtain the title compound (8.0 mg, 0.011 mmol) as a white solid. It was confirmed by measuring ¹H-NMR and ¹³C-NMR that this solid included two tautomers.

LCMS: m/z 757[M+H]⁺

HPLC retention time: 1.30 minutes (SMD-TFA05)

Major Tautomer

¹H-NMR (CDCl₃) 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).

¹³C-NMR (CDCl₃) 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 (CH₂), 66.9 (CH₂×2), 64.2 (qC), 57.5 (CH₂), 54.1 (CH₂×2), 51.9 (CH₂), 43.2 (CH₂), 31.9 (CH₂), 22.4 (CH₃), 19.1 (CH₂).

Minor Tautomer

¹H-NMR (CDCl₃) 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).

¹³C-NMR (CDCl₃) 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 (CH₂), 66.9 (CH₂×2), 64.2 (qC), 57.5 (CH₂), 54.1 (CH₂×2), 50.7 (CH₂), 44.0 (CH₂), 31.1 (CH₂), 21.8 (CH₃), 18.6 (CH₂).

The appropriate phenol intermediates of Examples 324, 325, and 327 and appropriate alcohol reagents were used, and operations similar to those of Example 156 were carried out to synthesize the compounds of the Examples described in the following Table.

TABLE 26

Example

LCMS
Retention time
m/z

No.
Structural formula
analysis condition No.
(min)
[M + H]⁺

158

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QC-SMD- TFA05
1.68
718

159

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QC-SMD- TFA05
1.69
718

160

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SMD- TFA05
1.17
727

161

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QC-SMD- TFA05
1.32
756

162

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QC-SMD- TFA05
1.61
730

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

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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. Subsequently, palladium acetate (1.79 mg, 0.0080 mmol), triisopropylsilanethiol (9.87 mg, 0.052 mmol), and 1,4-dioxane (0.4 mL) were further added, and the mixture was stirred at 110° C. for 2 hours.

After the reaction mixture was cooled to room temperature, 4-(2-chloroethyl)morpholine hydrochloric acid (37.1 mg, 0.199 mmol) was added to this reaction mixture, and after the resultant was heated at 100° C. for several hours, it was cooled to room temperature. This reaction mixture was purified by C18 reverse-phase column chromatography. A 4 N hydrogen chloride/1,4-dioxane solution was added to the obtained compound, and the solution was concentrated and dried to obtain the title compound (17 mg, 53%) as a white solid.

LCMS: m/z 772[M+H]⁺

HPLC retention time: 1.35 minutes (analysis condition 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]pyridazine-3-carboxamide hydrochloride

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First Step

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A solution of (bromomethyl)potassium 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 resultant was cooled to room temperature. After the reaction mixture was filtered and washed with acetone (15 mL), the solution was dried to obtain trifluoro(morpholinomethyl)potassium borate (68 mg, 66%) as a crude product.

Second Step

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) were added twice to a solution of trifluoro(morpholinomethyl)potassium borate (28.2 mg, 0.136 mmol) obtained in 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. overnight. After the reaction mixture was cooled to room temperature, this reaction mixture was purified by reverse-phase column chromatography. The obtained compound was dissolved in ethanol, then a 4 N hydrogen chloride/dioxane solution were added, and the resultant was dried to obtain the title compound (28 mg, 68%) as a white solid.

LCMS: m/z 726[M+H]⁺

HPLC retention time: 1.28 minutes (analysis condition QC-SMD-TFA05)

Major Tautomer

¹H-NMR (CDCl₃) 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

¹H-NMR (CDCl₃) 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

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Molybdenum hexacarbonyl (70.2 mg, 0.266 mmol), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (a 1:1 dichloromethane complex) (4.4 mg, 0.0053 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0024 mL, 0.159 mmol) were added to a 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) (40 mg, 0.053 mmol) in methanol (2 mL), and the mixture was stirred under nitrogen atmosphere at 70° C. for 4 hours. The reaction mixture was added to 1 N hydrochloric acid, the resultant was extracted with dichloromethane, and after the organic layer was dried over anhydrous magnesium sulfate, the resultant was filtered and concentrated at reduced pressure. The resultant residue was purified by preparative TLC (hexane:ethyl acetate=2:1) to obtain the title compound (29.3 mg, 81%) as light brown oil.

LCMS: m/z 685[M+H]⁺

HPLC retention time: 1.68 minutes (analysis condition QC-SMD-TFA05)

Reference Example 80
(4aR)—N-(4-Bromo-3,5-difluorophenyl)-4-hydroxy-4a-methyl-2-oxo-1,5,6,7-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide

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First Step

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A solution of 4-bromo-3,5-difluoroaniline (2.00 g, 9.62 mmol) and Meldrum's acid (2.77 g, 19.2 mmol) in toluene (18 mL) was stirred at 90° C. for 3 hours. After the reaction mixture was cooled to 0° C., the deposit was collected by filtration. The obtained solid was purified by reverse-phase column chromatography (0.1% formic acid water/acetonitrile) to obtain 3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate (2.00 g, 71%) as white powder.

LCMS: m/z 294[M+H]⁺

HPLC retention time: 0.66 minutes (analysis condition SQD-FA05)

Second Step

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2,4-Dimethoxybenzaldehyde, (R)-2-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride, and 3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate were used, and operations similar to those of Reference Example 1-1 were carried out to synthesize (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 minutes (analysis condition SQD-FA05)

Third Step

(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 the mixture was cooled to 0° C., trifluoromethanesulfonic acid (0.15 mL, 1.65 mmol) was added dropwise. After the mixture was stirred at room temperature for 30 minutes, the reaction mixture was added to ice-cold water (50 mL), neutralized with potassium carbonate (5.5 g, 39.8 mmol), and extracted three times with ethyl acetate (100 mL). After the organic layer was washed with a brine, the resultant was dried over sodium sulfate. The resultant was filtered, the filtrate was concentrated at reduced pressure, and the resultant residue was purified by C-18 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 minutes (analysis condition SQD-FA05)

Reference 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

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First Step

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4-(Trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Reference Example 42) (2.0 g) was dissolved in tetrahydrofuran (30 mL), tripotassium phosphate (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 for separation, and the organic layer was washed with a 12% brine and concentrated at reduced pressure to obtain propanedioic acid 3-O— [4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]1-O-methyl as a crude product.

LCMS: m/z 407[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition SQD-FA05)

Second Step

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Methanol (20 mL) and a 10 N aqueous sodium hydroxide solution (1.96 mL) were added to 3-O-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]phenyl]1-O-methyl obtained in First Step, and the mixture was stirred at room temperature for 10 hours. 6 N hydrochloric acid was added to adjust the pH to 3, ethyl acetate and water were added for separation, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled away at reduced pressure. Hexane (90 mL) and ethyl acetate (10 mL) were added to the resultant residue, the mixture was stirred and then filtered, and the resultant solid was dried to obtain 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanoate (2.34 g, two-step yield 91%).

LCMS: m/z 393[M+H]⁺

HPLC retention time: 0.29 minutes (analysis condition SQD-FA50)

Third Step

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(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 nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was concentrated at reduced pressure, toluene was added for azeotropic removal, 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 atmosphere at room temperature for 2 hours. After the reaction mixture was filtered, the resultant was concentrated at reduced pressure to obtain (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The obtained crude product was dissolved in acetic acid (200 mL) and methanol (30 mL), zinc powder (29.4 g, 4501 mmol) was added in divided portions under nitrogen stream, at 0° C., and it was added, and the mixture was stirred for 1 hour. Methanol (100 mL) was added to the reaction mixture, the mixture was filtered through a celite pad, and then the filtrate was concentrated at reduced pressure. After a similar operation was repeated twice, the resultant residue was purified by column chromatography on silica gel (dichloromethane/methanol). After a 4 N hydrogen chloride/1,4-dioxane solution was added to the obtained fraction, the resultant was concentrated at reduced pressure to obtain (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 minutes mass chromatogram (analysis condition SMD-TFA05)

Fourth Step

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(R)-2-Methyl-1-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2-carboxylic acid methyl ester and (R)-1-amino-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride were used as a reagent and a starting material, respectively, and operations similar to those of Second Step of Reference Example 1-1 were carried out to synthesize (R)-2-methyl-1-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2-carboxylic acid methyl ester.

LCMS: m/z 531[M−H]⁻

HPLC retention time: 0.88 minutes (SQD-FA05)

Fifth Step

(R)-2-Methyl-1-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)propanamide)pyrrolidine-2-carboxylic acid methyl ester was used, and operations similar to those of Third Step of Reference Example 1-1 were carried out to synthesize the title compound.

LCMS: m/z 501[M+H]⁺

HPLC retention time: 1.03 minutes (SQD-FA05)

Reference 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

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First Step

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4-(Trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Reference Example 50) and Meldrum's acid were used, and operations similar to those of Second Step of Reference Example 80 were carried out to synthesize 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoate.

Second Step

(R)-1-amino-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride and 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoate were used, and operations similar to those of Fourth and Fifth Steps of Reference Example 81 were carried out to synthesize the title compound.

LCMS: m/z 502[M+H]⁺

HPLC retention time: 1.02 minutes (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

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A 1.7 N toluene solution (0.0644 mL, 0.109 mmol) of 4-bromo-1-(bromomethyl)-2-fluorobenzene (14.7 mg, 0.055 mmol) and potassium 2,2-dimethylpropan-1-olate was added to a solution of (4aR)—N-(4-bromo-3,5-difluorophenyl)-4-hydroxy-4a-methyl-2-oxo-1,5,6,7-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxamide (Reference 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 purified directly by C18 reverse-phase column chromatography (0.1% formic acid acetonitrile/water) to obtain the title compound (6.0 mg, 20%) as a grayish white amorphous solid.

LCMS: m/z 588[M−H]⁻

HPLC retention time: 1.32 minutes (SQD-FA05)

The appropriate pyridazinone intermediates of Reference Examples 80 to 82 and appropriate benzylhalide reagents were used, and operations similar to those of Example 166 were carried out to synthesize the compounds of the Examples described in the following Table.

TABLE 27

Example

LCMS
Retention time
m/z

No.
Structural formula
analysis condition No.
(min)
[M + H]⁺

167

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QC-SMD- TFA05
1.65
657

168

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SQD-AA05
1.20
625

169

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SQD-AA05
1.19
625

170

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QC-SMD- TFA05
1.67
627

171

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QC-SMD- TFA05
1.68
627

172

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SQD-AA05
1.16
627

173

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QC-SMD- TFA05
1.67
627

174

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QC-SMD- TFA05
1.74
544

175

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QC-SMD- TFA05
1.66
651

176

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SQD-AA05
1.18
651

177

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QC-SMD- TFA05
1.68
658

178

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QC-SMD- TFA05
1.65
617

179

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QC-SMD- TFA05
1.64
617

180

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QC-SMD- TFA05
1.76
626

181

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QC-SMD- TFA05
1.76
626

182

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QC-SMD- TFA05
1.76
626

183

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QC-SMD- TFA05
1.68
650

184

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QC-SMD- TFA05
1.76
688

185

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QC-SMD- TFA05
1.76
606

186

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QC-SMD- TFA05
1.76
606

187

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QC-SMD- TFA05
1.77
606

188

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QC-SMD- TFA05
1.72
592

189

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QC-SMD- TFA05
1.76
676

190

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SQD-AA05
1.15
528

191

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SQD-AA05
1.16
528

192

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QC-SMD- TFA05
1.70
528

193

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SQD-AA05
1.15
528

194

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SQD-AA05
1.15
546

195

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QC-SMD- TFA05
1.76
524

196

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QC-SMD- TFA05
1.75
544

197

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QC-SMD- TFA05
1.73
546

198

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SQD-AA05
1.18
643

199

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QC-SMD- TFA05
1.67
609

200

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QC-SMD- TFA05
1.67
609

201

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SQD-AA05
1.18
643

202

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SQD-AA05
1.17
651

203

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QC-SMD- TFA05
1.66
627

204

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QC-SMD- TFA05
1.71
643

205

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SQD-AA05
1.21
623

206

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QC-SMD- TFA05
1.67
609

207

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QC-SMD- TFA05
1.68
610

208

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QC-SMD- TFA05
1.68
610

209

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QC-SMD- TFA05
1.72
644

210

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QC-SMD- TFA05
1.72
644

211

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QC-SMD- TFA05
1.71
644

212

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QC-SMD- TFA05
1.70
628

213

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QC-SMD- TFA05
1.71
628

214

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QC-SMD- TFA05
1.71
628

215

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QC-SMD- TFA05
1.76
624

216

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QC-SMD- TFA05
1.78
571

217

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QC-SMD- TFA05
1.77
589

218

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QC-SMD- TFA05
1.62
517

219

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QC-SMD- TFA05
1.76
526

220

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QC-SMD- TFA05
1.62
517

221

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QC-SMD- TFA05
1.76
526

222

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QC-SMD- TFA05
1.62
517

223

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QC-SMD- TFA05
1.76
526

224

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SQD-AA05
1.18
589

225

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QC-SMD- TFA05
1.68
590

226

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QC-SMD- TFA05
1.61
615

227

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SQD-AA05
1.11
615

228

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SQD-AA05
1.11
615

229

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QC-SMD- TFA05
1.67
644

230

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QC-SMD- TFA05
1.66
644

231

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QC-SMD- TFA05
1.71
627

232

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QC-SMD- TFA05
1.70
627

233

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QC-SMD- TFA05
1.70
645

Although the respective compounds described in this table include their tautomers, for example, ¹H-NMR of Example 196 is as follows.

Major Tautomer

¹H-NMR (400 MHz, CDCl₃) 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

¹H-NMR (400 MHz, CDCl₃) 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

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Methyl (4aR)-1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate (Reference Example 12) and 1,1,1-trifluoro-4-iodobutane were used, and operations similar to those of Third Step of Reference Example 80, Example 166, and Example 21 were consecutively carried out to obtain the title compound.

LCMS: m/z 612[M+H]⁺

HPLC retention time: 1.63 minutes (analysis condition 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

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Methyl (4aR)-1-[(2,4-dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate (Reference Example 12) and ethyl 7-bromoheptanoate were used, and operations similar to those of Example 234 were carried out to obtain the title compound.

LCMS: m/z 657[M+H]⁺

HPLC retention time: 1.70 minutes (analysis condition 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)pyrimidine-4-yl]phenyl-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

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First Step

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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. After the reaction mixture was cooled to room temperature, the precipitate was filtered for separation, and after the filtrate was washed with sodium thiosulfate and a brine, the resultant was dried over sodium sulfate. After the resultant was filtered, the filtrate was concentrated at reduced pressure to obtain 1-iodo-8-(2-(2-methoxyethoxy)ethoxy)octane (1.05 g, 91%) as yellow oil.

Second Step

Methyl (4aR)-1-[(2,4-(dimethoxyphenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate (Reference Example 12) and the iodine body obtained in First Step was used, and operations similar to those of Example 234 were carried out to obtain the title compound.

LCMS: m/z 732[M+H]⁺

HPLC retention time: 1.76 minutes (analysis condition 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 Step

Methyl (2S)-3,3-Dimethyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoate

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(S)-2-((Tert-butoxycarbonyl)amino)-3,3-dimethyl butanoic 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) were added, and the mixture was stirred under nitrogen atmosphere at 45° C. overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered, water was added, and the resultant was extracted with ethyl acetate. The organic layer was washed with a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (12.7 g, 100%).

¹H-NMR (CDCl₃) δ: 4.75 (1H, s), 3.71 (3H, s), 2.94 (3H, s), 1.48 (9H, s), 1.08 (9H, s).

Second Step

Methyl (S)-3,3-Dimethyl-2-(methylamino)butanoate hydrochloride

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Hydrochloric acid (a 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 at reduced pressure to obtain the title compound (9.58 g, 100%).

¹H-NMR (DMSO-D₆) δ: 9.00 (1H, brs), 3.89-3.86 (1H, m), 3.79 (3H, s), 2.54 (3H, s), 1.02 (9H, s).

Third Step

Methyl (2S)-2-[[(2,3-difluorophenyl)methylideneamino]-methylamino]-3,3-dimethylbutanoate

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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), sodium nitrite (33.4 mg, 0.393 mmol) was added at 0° C., and the mixture was stirred under nitrogen atmosphere 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 atmosphere for 4 hours. After the reaction mixture was 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 at reduced pressure and diluted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate solution and a brine, and then the resultant was dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (44.2 mg, 41%).

LCMS: m/z 299[M+H]⁺

HPLC retention time: 1.13 minutes (analysis condition SQD-AA05)

Fourth Step

(3S)-3-tert-Butyl-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyrimidine-5-carboxylic acid 2-methylpropyl ester

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Methyl ((2S)-2-[[(2,3-difluorophenyl)methylideneamino]-methylamino]-3,3-dimethylbutanoate (44.2 mg, 0.148 mmol)) was dissolved in hydrochloric acid (a methanol solution, 442 μL), borane-pyridine (29.9 μL, 0.296 mmol) was added at 0° C., and the mixture was stirred under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated at reduced pressure and diluted with ethyl acetate, the organic layer was washed with a 1 N aqueous dipotassium hydrogenphosphate solution and a brine, and the aqueous layer was separated by a phase separator and concentrated at reduced pressure to obtain methyl (2S)-2-[[(2,3-difluorophenyl)methylamino]-methylamino]-3,3-dimethylbutanoate as a crude product. The obtained 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-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (an ethyl acetate solution, 174 μL, 0.296 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere for 1 hour. Water was added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous dipotassium hydrogenphosphate solution and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain methyl (2S)-2-[[(2,3-difluorophenyl)methyl-[3-(2-methylpropoxy)-3-oxopropanoyl]amino]-methylamino]-3,3-dimethylbutanoate as a crude product. The obtained 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 nitrogen atmosphere at 80° C. for 2 hours. 1 N Hydrochloric acid was added to the reaction mixture at 0° C., and the resultant was extracted with ethyl acetate. The organic layer was washed with a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (48.1 mg, 79%).

LCMS: m/z 411.5[M+H]⁺

HPLC retention time: 1.03 minutes (analysis condition SQD-AA05)

Fifth Step

(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

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(3S)-3-tert-Butyl-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-2-methyl-6-oxo-3H-pyridazine-5-carboxylic acid 2-methylpropyl ester (6.3 mg, 0.015 mmol) was dissolved in toluene (200 μL), 4-chloro-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Reference Example 53) (4.2 mg, 0.015 mmol) was added, and the mixture was heated for 1 hour. The reaction mixture was concentrated and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (8.0 mg, 85%).

LCMS: m/z 610.3[M+H]⁺

HPLC retention time: 1.72 minutes (analysis condition QC-SMD-TFA05)

Reference Example 83
Methyl (S)-2-(ethylamino)-3,3-dimethylbutanoate hydrochloride

First Step

Methyl (2S)-2-[benzyl(ethyl)amino]-3,3-dimethylbutanoate

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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 sodium triacetoxyhydroborate (12.3 g, 58.0 mmol) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered, water was added, and the resultant 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 a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (2S)-2-(benzylamino)-3,3-dimethylbutanoate methyl ester (6.82 g) as a crude product. A part of the obtained 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 mmol) were added, and the mixture was stirred under 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 a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (1.65 g, 88%).

LCMS: m/z 264.3[M+H]⁺

HPLC retention time: 1.14 minutes (analysis condition SMD-TFA05)

Second Step

Methyl (S)-3,3-dimethyl-2-(methylamino)butanoate hydrochloride

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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-carbon (20 wt. %, 328 mg) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered, hydrochloric acid (a dioxane solution, 4.67 mL, 18.7 mmol) was added, and then the resultant was concentrated at reduced pressure to obtain the title compound (922 mg, 71%).

¹H-NMR (DMSO-D₆) 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).

Reference Example 84
Methyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoate

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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, 11.0 mmol) and diisopropylethylamine (4.79 mL, 27.5 mmol) were added, and the mixture was stirred under nitrogen atmosphere at 60° C. for 27 hours. After the mixture was cooled to room temperature, the reaction mixture was filtered, concentrated hydrochloric acid was added, the resultant was concentrated at reduced pressure, and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound as a solution of acetonitrile/water.

LCMS: m/z 228.3[M+H]⁺

HPLC retention time: 1.19 minutes (analysis condition SMD-TFA05)

Reference Example 85
Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride

First Step

Methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutanecarboxylate

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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) were added at 0° C., and the mixture was stirred under nitrogen atmosphere at room temperature for 3 hours. A 1 N aqueous hydrochloric acid solution was added to the reaction mixture at 0° C., and the mixture was extracted with diethyl ether. The organic layer was washed with water, a saturated sodium bicarbonate solution, a 10 wt. % aqueous sodium thiosulfate solution, and a brine, the aqueous layer was separated by a phase separator, the resultant was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (1.13 g, 100%).

LCMS: m/z 266.3[M+Na]⁺

HPLC retention time: 0.92 minutes (analysis condition SQD-AA05)

Second Step

Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride

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In a similar manner to Second Step of Example 237, the title compound was synthesized from methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutanecarboxylate.

¹H-NMR (DMSO-D₆) 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).

Reference Example 86
Methyl 1-(methylamino)cyclobutanecarboxylate 4-toluenesulfonate

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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, the mixture was concentrated at reduced pressure, ethyl acetate (15 mL) was added, and the resultant was filtered to obtain the title compound (1.96 g, 80%).

¹H-NMR (DMSO-D₆) 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).

Reference Example 87
Methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride

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In a similar manner to First and Second Steps of Reference Example 85, the title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid.

¹H-NMR (DMSO-D₆) 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).

Reference Example 88
Methyl 1-(methylamino)cyclopentanecarboxylate 4-toluenesulfonate

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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, the mixture was concentrated at reduced pressure, ethyl acetate (15 mL) was added, and the resultant was filtered to obtain the title compound (2.00 g, 78%).

¹H-NMR (DMSO-D₆) 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).

Reference Example 89
Methyl 1-(methylamino)cyclohexanecarboxylate hydrochloride

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In a similar manner to First and Second Steps of Reference Example 85, the title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid.

¹H-NMR (DMSO-D₆) 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]⁺

LCMS: m/z 172.5[M+H]⁺

HPLC retention time: 0.52 minutes (analysis condition SMD-TFA05)

Reference Example 90
Methyl 2-ethyl-2-(methylamino)butanoate hydrochloride

First Step

2-(((Benzyloxy)carbonyl)amino)-2-ethylbutanoate methyl ester

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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) were added, and the mixture was stirred at room temperature for 1.5 hours and at 95° C. for 0.5 hours. Benzyl alcohol (1.1 mL, 10.6 mmol) was added, and the mixture was stirred at 95° C. overnight. The reaction mixture was concentrated at reduced pressure, diluted with diethyl ether, and the resultant was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution, and a brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/hexane) to obtain the title compound (488.1 mg, 99%).

LCMS: m/z 280[M+H]⁺

HPLC retention time: 1.11 minutes (analysis condition SMD-TFA05)

Second Step

Methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-2-ethylbutanoate

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After a solution of methyl 2-(((benzyloxy)carbonyl)amino)-2-ethylbutanoate (481.3 mg, 1.72 mmol) in N,N-dimethylformamide (3.4 mL) was added to sodium hydride (83 mg, 3.45 mmol) at 0° C., 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, a saturated sodium bicarbonate solution, an aqueous sodium thiosulfate solution, and a brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/hexane) to obtain the title compound (438.5 mg, 87%).

LCMS: m/z 294[M+H]⁺

HPLC retention time: 1.14 minutes (analysis condition SMD-TFA05)

Third Step

Methyl 2-ethyl-2-(methylamino)butanoate hydrochloride

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Palladium-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 hydrogen atmosphere at room temperature for 1 hour. A hydrochloric acid-methanol solution (0.5 M, 14.8 mL) was added to the reaction mixture, and the resultant was filtered and concentrated at reduced pressure to obtain the title compound (281.9 mg, 97%).

¹H-NMR (CD₃OD) 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 minutes (analysis condition SMD-TFA05)

Reference Example 91
4-Chloro-5-methyl-6-(trifluoromethyl)pyrimidine

First Step

5-Methyl-6-(trifluoromethyl)pyrimidin-4(3H)-one

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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 hydrochloric acid and water were added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The resultant 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 minutes (analysis condition SQD-FA05)

Second Step

4-Chloro-5-methyl-6-(trifluoromethyl)pyrimidine

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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 resultant was extracted with dichloromethane. The organic layer was washed with a brine, dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure to obtain the title compound as a crude product.

LCMS: m/z 197[M+H]⁺

HPLC retention time: 0.95 minutes (analysis condition SMD-TFA05)

Reference Example 92
4,5-Dichloro-6-(trifluoromethyl)pyrimidine

First Step

5-Chloro-6-(trifluoromethyl)pyrimidin-4(3H)-one

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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 a brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by C18 reverse-phase column chromatography (water/acetonitrile, 0.1% formic acid) to obtain the title compound (368.5 mg, 31%).

LCMS: m/z 199[M+H]⁺

HPLC retention time: 0.68 minutes (analysis condition SMD-TFA05)

Second Step

4,5-Dichloro-6-(trifluoromethyl)pyrimidine

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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 1.5 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 at 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 minutes (analysis condition SMD-TFA05)

Reference Example 93
4-Chloro-2-(6-chloropyrimidin-4-yl)aniline

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Dioxane (9.6 mL) was added to 2-amino-4-chloro-phenylboronic acid pinacol 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 at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate/hexane) to obtain the title compound (349.6 mg, 59%).

LCMS: m/z 240[M+H]⁺

HPLC retention time: 1.14 minutes (analysis condition SMD-TFA05)

The boronic acid derivatives and halides described in the following Table were used to synthesize the aniline intermediates described in the following Table by carrying out operations similar to those of Reference Example 93.

TABLE 28

Reference

Aniline

Example

Boronic acid

intermediate

No.
Aniline
derivative
Halide
m/z

94

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251 [M + H]⁺

95

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255 [M + H]⁺

96

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322 [M + H]⁺

97

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342 [M + H]⁺

98

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345 [M + H]⁺

Reference Example 99
6-(2-Amino-5-chlorophenyl)pyrimidine-4-carbonitrile

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4-Chloro-2-(6-chloropyrimidin-4-yl)aniline was used, and operations similar to those of Reference Example 63 were carried out to synthesize the title compound.

LCMS: m/z 265[M+H]⁺

HPLC retention time: 1.16 minutes (analysis condition SMD-TFA05)

Reference Example 100
6-(2-Amino-5-chlorophenyl)-5-methylpyrimidine-4-carbonitrile

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4-Chloro-2-(6-chloropyrimidin-4-yl)aniline was used, and operations similar to those of Reference Example 63 were carried out to synthesize the title compound.

LCMS: m/z 245[M+H]⁺

HPLC retention time: 0.75 minutes (analysis condition SQD-FA05)

Examples 238 to 300

The appropriate aniline reagents of Reference Examples 94 to 100 described in Table 30, the appropriate benzaldehyde derivatives of Reference Example 3 and those known from literature or commercialized, and the appropriate amines of Reference Examples 85 to 90 and those known from literature or commercialized were used to synthesize the compounds described in the following Table by carrying out operations similar to those of Third to Fifth Steps of Example 237.

Purification condition: HPLC

Mobile phase: MeCN/water (no additive), MeCN/water (0.1% formic acid), MeCN/water (0.1% NEt₃), or CHCl₃

Column:

- YMC-Actus ODS-A (100×20 mml.D., S-5 μm, 12 nm)
- YMC-Actus Triart C18 (100×30 mml.D., S-5 μm, 12 nm)
- YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)
- JAI JAIGEL-H (600×20 mml.D., GPC)

TABLE 29

LCMS

analysis
Retention

Example

condition
time
m/z

No.
Structural formula
No.
(min)
[M + H]⁺

238

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QC-SMD- TFA05
1.71
643

239

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QC-SMD- TFA05
1.71
609

240

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SQD- AA05
1.72
544

241

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QC-SMD- TFA05
1.74
523

242

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QC-SMD- TFA05
1.72
577

243

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QC-SMD- TFA05
1.75
576

244

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QC-SMD- TFA05
1 .65
499

245

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QC-SMD- TFA05
1.75
623

246

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QC-SMD- TFA05
1.78
558

247

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QC-SMD- TFA05
1.71
677

248

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SQD- AA05
1.59
612

249

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QC-SMD- TFA05
1.69
630

250

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QC-SMD- TFA05
1.69
596

251

embedded image

QC-SMD- TFA05
1.67
595

252

embedded image

QC-SMD- TFA05
1.69
630

253

embedded image

QC-SMD- TFA05
1.68
629

254

embedded image

QC-SMD- TFA05
1.70
530

255

embedded image

QC-SMD- TFA05
1.69
594

256

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QC-SMD- TFA05
1.68
593

257

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QC-SMD- TFA05
1.71
528

258

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QC-SMD- TFA05
1.69
561

259

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QC-SMD- TFA05
1.70
507

260

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SQD- AA05
1.20
642

261

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SQD-AA05
1.23
608

262

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QC-SMD- TFA05
1.74
521

263

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QC-SMD- TFA05
1.72
575

264

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QC-SMD- TFA05
1.36
773

265

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QC-SMD- TFA05
1.35
739

266

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QC-SMD- TFA05
1.36
772

267

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QC-SMD- TFA05
1.34
738

268

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QC-SMD- TFA05
1.36
750

269

embedded image

QC-SMD- TFA05
1.33
716

270

embedded image

QC-SMD- TFA05
1.31
744

271

embedded image

QC-SMD- TFA05
1.30
729

272

embedded image

QC-SMD- TFA05
1.28
696

273

embedded image

QC-SMD- TFA05
1.26
774

274

embedded image

QC-SMD- TFA05
1.30
710

275

embedded image

QC-SMD- TFA05
1.33
719

276

embedded image

QC-SMD- TFA05
1.36
753

277

embedded image

QC-SMD- TFA05
1.34
695

278

embedded image

QC-SMD- TFA05
1.38
787

279

embedded image

QC-SMD- TFA05
1.33
759

280

embedded image

QC-SMD- TFA05
1.32
758

281

embedded image

QC-SMD- TFA05
1.30
724

282

embedded image

QC-SMD- TFA05
1.31
756

283

embedded image

QC-SMD- TFA05
1.27
728

284

embedded image

QC-SMD- TFA05
1.35
791

285

embedded image

QC-SMD- TFA05
1.33
771

286

embedded image

QC-SMD- TFA05
1.33
737

287

embedded image

QC-SMD- TFA05
1.34
770

288

embedded image

QC-SMD- TFA05
1.32
736

289

embedded image

QC-SMD- TFA05
1.34
748

290

embedded image

QC-SMD- TFA05
1.35
785

291

embedded image

QC-SMD- TFA05
1.36
773

292

embedded image

QC-SMD- TFA05
1.34
739

293

embedded image

QC-SMD- TFA05
1.35
772

294

embedded image

QC-SMD- TFA05
1.33
738

295

embedded image

SMD- TFA05
1.35
785

296

embedded image

SMD- TFA05
1.35
799

297

embedded image

SMD- TFA05
1.33
751

298

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SMD- TFA05
1.33
718

Reference Example 101
Methyl 2-(2,3-difluorobenzyl)-5-hydroxy-6,6-dimethyl-3-oxo-1-phenyl-1,2,3,6-tetrahydropyridazine-4-carboxylate

First Step

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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 atmosphere at 110° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain a crude product. Methanol (6 mL) and 2,3-difluoro-benzaldehyde (0.77 mL, 7.1 mmol) were added to the obtained crude product, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure, and the resultant residue was purified by C-18 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-phenylhydrazinyl)-2-methylpropanoate (0.51 g, 21%) as yellow oil.

LCMS: m/z 347[M+H]⁺

HPLC retention time: 1.12 minutes (analysis condition SQD-FA05)

Second Step

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Ethyl 2-(2-(2,3-difluorobenzylidene)-1-phenylhydrazinyl)-2-methylpropanoate obtained in First Step was used, and operations similar to those of Reference Example 1-2 were carried out to obtain the title compound (0.38 g, 65%) as yellow oil.

LCMS: m/z 403[M+H]⁺

HPLC retention time: 0.97 minutes (analysis condition SQD-FA05)

Reference Example 102
Methyl 6-(2,3-difluorobenzyl)-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylate

First Step

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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 at reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain a crude product. The obtained crude product was added to the reaction mixture, and then methanol (2 mL) and 2,3-difluoro-benzaldehyde (0.12 mL, 1.1 mmol) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure, and the resultant residue was purified by C-18 reverse-phase column chromatography on silica gel (0.1% formic acid water/0.1% formic acid acetonitrile) to obtain ethyl 1-(2-(2,3-difluorobenzylidene)-1-methylhydrazinyl)cyclobutanecarboxylate (36 mg, 11%) as colorless oil.

LCMS: m/z 297[M+H]⁺

HPLC retention time: 1.15 minutes (analysis condition SQD-FA05)

Second Step

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Ethyl 1-(2-(2,3-difluorobenzylidene)-1-methylhydrazinyl)cyclobutanecarboxylate obtained in First Step was used, and operations similar to those of Second Step of Reference Example 101 were carried out to obtain the title compound (50 mg, 78%) as red oil.

LCMS: m/z 353[M+H]⁺

HPLC retention time: 0.93 minutes (analysis condition SQD-FA05)

Reference Example 103
Methyl 2-(2,3-difluorobenzyl)-5-hydroxy-1,6,6-trimethyl-3-oxo-1,2,3,6-tetrahydropyridazine-4-carboxylate

First Step

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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 (0.84 g, 6.5 mmol) was added, and the mixture was stirred and heated under nitrogen atmosphere at 60° C. for 66 hours. After the reaction mixture was cooled to room temperature, methanol (60 mL) and 2,3-difluoro-benzaldehyde (0.55 mL, 5.0 mmol) were added to the reaction mixture, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure, and the resultant residue was purified by C-18 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%) as colorless oil.

LCMS: m/z 285[M+H]⁺

HPLC retention time: 1.00 minute (analysis condition SQD-FA05)

Second Step

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Ethyl 2-[2-(2,3-difluorobenzylidene)-1-methylhydrazinyl]-2-methylpropionate obtained in First Step was used, and operations similar to those of Second Step of Reference Example 101 were carried out to obtain the title compound (650 mg, 68%) as yellow oil.

LCMS: m/z 341[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition SQD-FA05)

The appropriate aniline reagents and appropriate ester intermediates of Reference Examples 101 to 103 were used to synthesize the compounds described in the following Table by carrying out operations similar to those of Fifth Step of Example 237.

TABLE 30

LCMS

Example

analysis condition
Retention time
m/z

No.
Structural formula
No.
(min)
[M + H]⁺

299

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QC-SMD- TFA05
1.73
678

300

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QC-SMD- TFA05
1.68
628

301

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QC-SMD- TFA05
1.67
627

302

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QC-SMD- TFA05
1.56
602

303

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QC-SMD- TFA05
1.58
573

304

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QC-SMD- TFA05
1.59
616

305

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QC-SMD- TFA05
1.63
615

306

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QC-SMD- TFA05
1.58
616

307

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QC-SMD- TFA05
1.63
615

308

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QC-SMD- TFA05
1.62
653

309

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QC-SMD- TFA05
1.63
581

310

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QC-SMD- TFA05
1.65
593

311

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QC-SMD- TFA05
1.59
587

312

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QC-SMD- TFA05
1.62
607

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 Step

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Methylhydrazine, ethyl 2-bromo-2-methylpropionate, and the aldehyde reagent synthesized in Reference Example 3 were used, and operations similar to those of First Step of Reference Example 103 were carried out 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 minutes (analysis condition SMD-TFA05)

Second Step

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Ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzylidene)-1-methylhydrazinyl)-2-methylpropanoate (50 mg, 0.12 mmol) obtained in First Step was dissolved in a 10% hydrochloric acid-methanol 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 at reduced pressure, a 1 N aqueous dipotassium hydrogenphosphate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled away at reduced pressure to obtain ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)-2-methylpropanoate as a crude product.

LCMS: m/z 416[M+H]⁺

HPLC retention time: 0.63 minutes (analysis condition SMD-TFA05)

Third Step

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The crude product of ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)-2-methylpropanoate obtained in Second Step was dissolved in ethyl acetate (800 μL), and then the carboxylic acid reagent synthesized in First Step of Reference Example 82, pyridine (20 μL, 0.242 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (an ethyl acetate solution, 92 μL, 0.145 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere overnight. Water was added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain 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 a crude product.

LCMS: m/z 791[M+H]⁺

HPLC retention time: 1.19 minutes (analysis condition SMD-TFA05)

Fourth Step

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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 Third Step was used, and operations similar to those of Third Step of Reference Example 1-1 were carried out to synthesize the title compound (35.1 mg, 39% three-step yield).

LCMS: m/z 745[M+H]⁺

HPLC retention time: 1.27 minutes (analysis condition 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

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Ethyl 2-(2-(2,3-difluoro-4-(2-morpholinoethoxy)benzyl)-1-methylhydrazinyl)-2-methylpropanoate synthesized in Second Step of Example 313 and the carboxylic acid reagent synthesized in First Step of Reference Example 81 were used, and operations similar to those of Example 313 were carried out to synthesize the title compound (36.6 mg, 41% three-step yield).

LCMS: m/z 744[M+H]⁺

HPLC retention time: 1.28 minutes (analysis condition QC-SMD-TFA05)

Example 315
2-[[2,3-Difluoro-4-(3-morpholin-4-ylprop-1-ynil)phenyl]methyl]-5-hydroxy-1,6,6-trimethyl-3-oxo-N-[4-(trifluoromethyl)-2-(trifluoromethyl)pyrimidin-4-yl]phenyl]pyridazine-4-carboxamide

First Step

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2,3-Difluoro-4-iodobenzaldehyde and 3-isobutyloxy-3-oxopropionate were used, and operations similar to those of First and Second Steps of Reference Example 103 were carried out 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 minutes (analysis condition SQD-FA05)

Second Step

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(2-(2,3-Difluoro-4-iodobenzyl)-5-hydroxy-1,6,6-trimethyl-3-oxo-1,2,3,6-tetrahydropyridazine-4-carboxylic acid isobutyl ester synthesized in First Step and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Reference Example 50) were used, and operations similar to those of Fifth Step of Example 237 were carried out 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 minutes (analysis condition SQD-FA05)

Third Step

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The iodine body synthesized in Second Step and 4-(prop-2-yn-1-yl)morpholine were used, and operations similar to those of Example 123 were carried out to synthesize the title compound.

LCMS: m/z 739[M+H]⁺

HPLC retention time: 1.31 minutes (analysis condition 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-ynil)phenyl]methyl-5-hydroxy-1,6,6-trimethyl-3-oxopyridazine-4-carboxamide

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The aniline reagent synthesized in Reference Example 53 was used, and operations similar to those of Example 315 were carried out to synthesize the title compound.

LCMS: m/z 705[M+H]⁺

HPLC retention time: 1.29 minutes (analysis condition 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-ene-8-carboxamide

First Step

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate

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Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride (Reference 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 (132 mg, 1.91 mmol) was added at 0° C., 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 nitrogen atmosphere for 1.5 hours. After the reaction mixture was filtered, methanol (9.56 mL) and 2,3-difluoro-4-(2-morpholinoethoxy)benzaldehyde (324 mg, 1.19 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated at reduced pressure and diluted with ethyl acetate, the organic layer was washed with a 1 M aqueous dipotassium hydrogenphosphate solution and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (aminosilica, hexane/ethyl acetate) to obtain the title compound (402 mg, 82%).

LCMS: m/z 412[M+H]⁺

HPLC retention time: 0.91 minutes (analysis condition SMD-TFA05)

Second Step

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

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Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate (27.5 g, 66.9 mmol) was dissolved in ethyl acetate (158 mL), and then hydrochloric acid (a 4 M ethyl acetate solution, 158 mL) was added at 0° C., and the mixture was stirred under nitrogen atmosphere for 10 minutes. 5-Ethyl-2-methylpyridine borane (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. After an aqueous sodium hydroxide solution (5 M, 115 mL) and an aqueous potassium phosphate solution (1 M, 50.0 mL) were added to the reaction mixture, the mixture was diluted with ethyl acetate, the organic layer was washed with a 1 M aqueous dipotassium hydrogenphosphate solution and a brine, dried over magnesium sulfate, filtered, and concentrated at reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylamino]-methylamino]cyclobutane-1-carboxylate as a crude product. The obtained crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (First Step of Reference Example 82) (27.6 g, 70.2 mmol) were dissolved in ethyl acetate (279 mL) and N,N-dimethylformamide (139 mL), and then pyridine (5.40 mL, 66.9 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (a 1.7 M ethyl acetate solution, 79.0 mL, 134 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere for 30 minutes. A brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1 M aqueous dipotassium hydrogenphosphate solution and a brine, dried over magnesium sulfate, filtered, and concentrated at reduced pressure to obtain the title compound (1.15 g, 100%).

LCMS: m/z 789.1[M+H]⁺

HPLC retention time: 1.01 minutes (analysis condition SMD-FA05)

Third Step

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

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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) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 1.5 hours. Formic acid and water were added to the reaction mixture, and the mixture was purified by C18 reverse-phase column chromatography (methanol/water) to obtain the title compound (840 mg, 76%).

LCMS: m/z 757.4[M+H]⁺

HPLC retention time: 1.27 minutes (analysis condition SMD-TFA05)

Although tautomers of some of the title compounds exist, isomers may be observed in some cases and not in other cases according to the type of the solvent for measurement. For example, ¹H-NMR and ¹³C-NMR of major tautomers in chloroform-D are as follows.

Example 317
Major Tautomer

¹H-NMR (CDCl₃) 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, J_CF=7.2, 1.6 Hz), 6.72 (1H, ddd, J=8.6, J_CF=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).

¹³C-NMR (CDCl₃) 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 (CH₂), 66.9 (CH₂×2), 64.2 (qC), 57.5 (CH₂), 54.1 (CH₂×2), 41.6 (CH₂), 35.1 (CH₃), 32.4 (CH₂), 24.5 (CH₂), 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 Step

Methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate

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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) was added at 0° C., and the mixture was stirred under 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 nitrogen atmosphere for 1.5 hours. After the reaction 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 at reduced pressure and diluted with ethyl acetate, the organic layer was washed with a 1 M aqueous dipotassium hydrogenphosphate solution and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (aminosilica, hexane/ethyl acetate) to obtain the title compound (375 mg, 80%).

LCMS: m/z 426.2[M+H]⁺

HPLC retention time: 0.93 minutes (analysis condition SMD-TFA05)

Second Step

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

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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 (a 4 M ethyl acetate solution, 172 mL) was added at 0° C., and the mixture was stirred under nitrogen atmosphere for 10 minutes. 5-Ethyl-2-methylpyridine borane (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. After an aqueous sodium hydroxide solution (5 M, 125 mL) and an aqueous potassium phosphate solution (1 M, 50.0 mL) were added to the reaction mixture, the mixture was diluted with ethyl acetate, the organic layer was washed with a 1 M aqueous potassium phosphate solution and a brine, dried over magnesium sulfate, filtered, and concentrated at reduced pressure to obtain methyl 1-[[[2,3-difluoro-4-(2-morpholin-4-ylethoxy)phenyl]methylamino]-methylamino]cyclopentane-1-carboxylate as a crude product.

The obtained crude product and 3-oxo-3-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]anilino]propanoate (First Step of Reference Example 82) (29.0 g, 73.8 mmol) were dissolved in ethyl acetate (293 mL) and N,N-dimethylformamide (146 mL), and then pyridine (5.67 mL, 70.3 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (a 1.7 M ethyl acetate solution, 83.0 mL, 141 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere for 30 minutes. A brine was added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was washed with a 1 M aqueous dipotassium hydrogenphosphate solution and a brine, dried over magnesium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was washed with methanol to obtain the title compound (39.4 g, 70%).

LCMS: m/z 803.1[M+H]⁺

HPLC retention time: 1.03 minutes (analysis condition SMD-FA05)

Third Step

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

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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) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 1.5 hours. Formic acid and water were added to the reaction mixture, and the mixture was purified by C18 reverse-phase column chromatography (methanol/water) to obtain the title compound (13.3 g, 92%).

LCMS: m/z 771.3[M+H]⁺

HPLC retention time: 1.29 minutes (analysis condition SMD-TFA05)

Although tautomers of some of the title compounds exist, isomers may be observed in some cases and not in other cases according to the type of the solvent for measurement. For example, H-NMR and ¹³C-NMR of major tautomers in chloroform-D are as follows.

Example 318
Major Tautomer

¹H-NMR (CDCl₃) 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).

¹³C-NMR (CDCl₃) 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 (CH₂), 66.9 (CH₂×2), 57.5 (CH₂), 54.2 (CH₂×2), 41.7 (CH₂), 37.6 (CH₂), 36.8 (CH₂), 31.4 (CH₂), 24.8 (CH₂), 23.3 (CH₂).

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

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First Step

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(R)-2-Methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluorobenzaldehyde were used, and then (R)-1-((2,3-difluoro-4-iodobenzylidene)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester (2.24 g, 5.49 mmol) obtained by carrying out operations similar to those of Example 1 was dissolved in acetic acid (5.0 mL) and methanol (5.5 mL), and then sodium cyanoborohydride (1.76 g, 28.0 mmol) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 14 hours. A saturated sodium bicarbonate solution was added to the reaction mixture, and the resultant was concentrated at reduced pressure and extracted with ethyl acetate. The organic layer was washed with a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (R)-1-((2,3-difluoro-4-iodobenzyl)amino)-2-methylpyrrolidine-2-carboxylic acid methyl ester as a crude product.

Second Step

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The crude product obtained in First Step was dissolved in tetrahydrofuran (5.5 mL), and then tripotassium phosphate (2.38 g, 11.2 mmol) and chlorocarbonyl-acetic acid methyl ester (1.00 mL, 9.06 mmol) were added at 0° C., and the mixture was stirred under nitrogen atmosphere at room temperature for 3 hours. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain (S)-1-[(3-fluoro-benzyl)-(2-methoxycarbonyl-acetyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester as a crude product.

Third Step

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The obtained 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. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure to obtain 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 Step

The crude product (328 mg, 0.686 mmol) obtained in 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 hour. After the reaction mixture was left to cool, it was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (402 mg, 92%) as a grayish white solid.

LCMS: m/z 479[M+H]⁺

HPLC retention time: 0.97 minutes (analysis condition 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]pyridazine-3-carboxamide

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(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 2-methylpropyl ester (Reference Example 5) (100 mg, 0.192 mmol) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Reference Example 42) (73.6 mg, 0.240 mmol) were dissolved in toluene (0.96 mL), and the mixture was stirred at 100° C. for 40 minutes. After the reaction mixture was left to cool, it was concentrated at reduced pressure, and the resultant 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 minutes (analysis condition SQD-FA50)

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

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(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 2-methylpropyl ester (Reference Example 5) and 2′,3′-dimethoxy-5-(trifluoromethyl)-[1,1′-biphenyl]-2-amine (Reference Example 16) were used, and operations similar to those of Fourth Step of Example 319 were carried out to synthesize the title compound.

LCMS: m/z 744[M+H]⁺

HPLC retention time: 1.19 minutes (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]pyridazine-3-carboxamide

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First Step

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2,6-Difluoro-4-iodobenzaldehyde was used, and operations similar to those of First to Third Steps of Example 319 were carried out to synthesize (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 2-methylpropyl ester.

LCMS: m/z 521[M+H]⁺

HPLC retention time: 1.51 minutes (analysis condition SMD-TFA05)

Second Step

(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 2-methylpropyl ester and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yl)aniline (Reference Example 42) were used, and operations similar to those of Fourth Step of Example 319 were carried out to synthesize the title compound.

LCMS: m/z 753[M+H]⁺

HPLC retention time: 1.76 minutes (analysis condition QC-SMD-TFA05)

Example 323
(4aR)-1-[(2,3-Difluoro-4-iodophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-N-[4-(trifluormethyl)-2-[6-(trifluormethyl)pyrimidin-4-yl]phenyl]-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxamide

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(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 2-methylpropyl ester (Reference Example 5) and 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (Reference Example 50) were used, and operations similar to those of Fourth Step of Example 319 were carried out to synthesize the title compound.

LCMS: m/z 754[M+H]⁺

HPLC retention time: 0.93 minutes (analysis condition SQD-FA50)

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]pyridazine-3-carboxamide

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(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 2-methylpropyl ester (Reference 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) were dissolved in dimethylsulfoxide (4.1 mL) under nitrogen atmosphere, tetrabutylammonium hydroxide (4.24 g, 6.54 mmol) and water (1.56 mL) were added, and the mixture was stirred under nitrogen atmosphere at 100° C. for 5 hours. After the reaction mixture was left to cool, 1 N hydrochloric acid (5.1 mL), water (30 mL), and an appropriate amount of N-acetyl-L-cysteine were added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel to obtain the title compound (834 mg, 90%) as a pale yellow amorphous solid.

LCMS: m/z 643[M+H]⁺

HPLC retention time: 1.12 minutes (analysis condition 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

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(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) was used, and operations similar to those of Example 324 were carried out to synthesize the title compound.

LCMS: m/z 634[M+H]⁺

HPLC retention time: 1.14 minutes (analysis condition 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]pyridazine-3-carboxamide

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(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) was used, and operations similar to those of Example 324 were carried out to synthesize the title compound.

LCMS: m/z 643[M+H]⁺

HPLC retention time: 1.12 minutes (analysis condition 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]pyridazine-3-carboxamide

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(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) was used, and operations similar to those of Example 324 were carried out to synthesize the title compound.

LCMS: m/z 644[M+H]⁺

HPLC retention time: 1.11 minutes (analysis condition 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]pyridazine-3-carboxamide

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First Step

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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 nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was concentrated at reduced pressure, toluene was added for azeotropic removal, 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 atmosphere at room temperature for 2 hours. The reaction mixture was filtered and then concentrated at reduced pressure to obtain (S)-1-nitroso-pyrrolidine-2-carboxylic acid methyl ester as a crude product. The obtained crude product (362 mg, 2.10 mmol) was dissolved in acetic acid (10 mL) and methanol (1.0 mL), and then zinc (725 mg, 11.2 mmol) was added at 9° C., and the mixture was stirred under nitrogen atmosphere at 9° C. for 1 hour. After the reaction mixture was filtered through a celite pad, the filtrate was concentrated at reduced pressure. Methanol (1.0 mL) and 2,4-dichloro-4-hydroxybenzaldehyde (200 mg, 1.05 mmol) were added to the resultant residue, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and then concentrated at reduced pressure, and the resultant was extracted with ethyl acetate. The organic layer was washed with water and a brine, dried over sodium sulfate, filtered, and concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain methyl (R)-1-((2,6-dichloro-4-hydroxybenzylidene)amino)-2-methylpyrrolidine-2-carboxylate. The obtained product (5.3 g, 16.0 mmol) was dissolved in acetonitrile (50 mL), and then 2-(chloromethoxy)ethyl trimethylsilane (3.2 g, 19.2 mmol) and cesium carbonate (6.3 g, 19.3 mmol) were added, 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 resultant was extracted with ethyl acetate (100 mL) three times. The organic layer was washed with water and a brine, and then dried over sodium sulfate. The sodium sulfate was filtered off and the resultant was concentrated at reduced pressure to obtain a crude product of methyl (R)-1-((2,6-dichloro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzylidene)amino)-2-methylpyrrolidine-2-carboxylate as a white solid. The obtained crude product was used to obtain methyl (R)-1-N-(2,6-dichloro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylate by carrying out First and Second Steps of Reference Example 1-1.

LCMS: m/z 461[M+H]⁺

HPLC retention time: 4.73 minutes (analysis condition Ph-SMD-TFA05)

Second Step

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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 at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain methyl (R)-1-N-(2,6-dichloro-4-hydroxybenzyl)-3-isobutoxy-3-oxopropanamide)-2-methylpyrrolidine-2-carboxylate (5.0 g, 91%). The obtained 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 operations similar to those of Third Step of Reference Example 1-1 were carried out to obtain (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 2-methylpropyl ester.

LCMS: m/z 443[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition SMD-TFA05)

Third Step

(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 2-methylpropyl ester and 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine (Reference Example 70) were used, and operations similar to those of Example 21 were carried out to obtain the title compound.

LCMS: m/z 677[M+H]⁺

HPLC retention time: 1.51 minutes (analysis condition 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]pyridazine-3-carboxamide

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(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 2-methylpropyl ester (Second Step of Example 328) and 6,6′-bis(trifluoromethyl)-[2,3′-bipyridine]-3-amine (Reference Example 44) were used, and operations similar to those of Third Step of Example 328 were carried out to obtain the title compound.

LCMS: m/z 676[M+H]⁺

HPLC retention time: 1.55 minutes (analysis condition 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]pyridazine-3-carboxamide

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First Step

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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 (Third Step of Example 319) and 2-(trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-5-amine (Reference Example 70) were used, and operations similar to those of Fourth Step of Example 319 were carried out to synthesize ((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]pyridazine-3-carboxamide.

LCMS: m/z 755[M+H]⁺

HPLC retention time: 1.05 minutes (analysis condition SMD-TFA50)

Second Step

The iodide derivative obtained in First Step was used, and operations similar to those of Example 324 were carried out to synthesize the title compound.

LCMS: m/z 645[M+H]⁺

HPLC retention time: 1.43 minutes (analysis condition 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

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First Step

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(R)-2-Methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride and 2,3-difluorobenzaldehyde were used, and operations similar to those of First to Third Steps of Example 319 were carried out 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 Step

Methyl (4aR)-1-[(2,3-difluorophenyl)methyl]-4-hydroxy-4a-methyl-2-oxo-6,7-dihydro-5H-pyrrolo[1,2-b]pyridazine-3-carboxylate and 4-bromo-2-iodoaniline were used as reagents, and operations similar to those of Example 21 were carried out to synthesize the title compound.

LCMS: m/z 618[M+H]⁺

HPLC retention time: 1.16 minutes (analysis condition SMD-TFA05)

Reference Example 104
Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate hydrochloride

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Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-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 atmosphere for 30 minutes. Heptane (1.50 mL) and a seed crystal (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, the mixture was stirred for 16 hours, and then the deposited crystal was collected by filtration to obtain the title compound (271 mg, 88%).

Melting point: 108° C.

¹H-NMR (DMSO-D₆) 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 crystal used in Reference Example 104 was obtained by the following method.

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate (75.3 mg, 0.182 mmol) was dissolved in dimethylsulfoxide (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 obtained powder at 25° C., and the mixture was stirred for 4 days to obtain a deposit.

Reference Example 105
Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate hydrochloride

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Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-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 atmosphere for 30 minutes. Heptane (1.00 mL) and a seed crystal (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 for 2 hours, and the deposited crystal was collected by filtration to obtain the title compound (225 mg, 69%).

Melting point: 97° C.

¹H-NMR (DMSO-D₆) 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 crystal used in Reference Example 105 was obtained by the following method.

Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-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 atmosphere for 30 minutes. Heptane (0.500 mL) and methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclobutane-1-carboxylate hydrochloride (1.00 mg, 0.00222 mmol) were added to the reaction mixture, and the mixture was stirred for 1 hour. The deposited crystal was collected by filtration to obtain a deposit (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

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First Step

7-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid 2-methylpropyl ester

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2,3-Difluoro-4-hydroxybenzaldehyde and methyl 1-(methylamino)cyclopentanecarboxylate hydrochloride (Reference Example 87) were used to synthesize the title compound by a method similar to that of Reference Example 1-1.

LCMS: m/z 411 [M+H]⁺

HPLC retention time: 1.18 minutes (SMD-TFA05)

Second Step

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7-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid 2-methylpropyl ester and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]aniline (Reference 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 with reference to Example 21.

LCMS: m/z 658[M+H]⁺

HPLC retention time: 1.57 minutes (SMD-TFA05)

Third Step

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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., a 1 N-aqueous hydrochloric acid solution (0.063 mL, 0.375 mmol) was added, and the mixture was stirred for 10 minutes. The resultant was diluted with N,N-dimethyl formamide (0.6 mL) and purified by HPLC to obtain 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 condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 758[M+H]⁺

HPLC retention time: 1.72 minutes (SMD-FA05)

Fourth Step

Potassium trimethylsilanolate (5.38 mg, 0.042 mmol) was added to a 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. After the reaction mixture was concentrated, the resultant was diluted with N,N-dimethyl formamide (0.6 mL) and purified by HPLC to obtain the title compound (6.2 mg, 60%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 744[M+H]⁺

HPLC retention time: 1.60 minutes (SMD-FA05)

In Examples 333 to 335, appropriate alkyl bromides were used, and operations similar to those of Example 332 were carried out to synthesize the compounds described in the following Table.

TABLE 31

LCMS
Retention

Example

Analysis
time
m/z

No.
Structural formula
condition
(min)
[M + H]⁺

333

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SMD-FA05
1.62
758

334

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SMD-TFA05
1.64
772

335

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SMD-TFA05
1.67
786

Reference Example 106
6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylic acid 2-methylpropyl ester

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Methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride was used as a starting material (Reference Example 85) to synthesize the title compound by a method similar to that of Example 332.

LCMS: m/z 411[M+H]⁺

HPLC retention time: 1.18 minutes (SMD-TFA05)

Reference Example 107
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

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Methyl 1-(methylamino)cyclobutane-1-carboxylate hydrochloride was used as a starting material to synthesize the title compound by a method similar to that of Example 332.

LCMS: m/z 658[M+H]⁺

HPLC retention time: 1.48 minutes (SMD-TFA05)

Example 336
8-[[2,3-Difluoro-4-(2-morpholin-2-oxo-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

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The title 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-yl-ethanone (Kapanda, Coco N. Journal of Medicinal Chemistry, 52 (22), 7310-7314; 2009) by a method similar to that of Third Step of Example 322.

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.43 minutes (analysis condition 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

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The title 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 of Example 407.

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.38 minutes (analysis condition SMD-TFA05)

Reference 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-ene-8-carboxamide

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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 (Reference Example 107) (3.00 g, 4.66 mmol) was dissolved in acetone (23.3 mL), then 1,2-dibromoethane (6.85 mL, 79.0 mmol) and potassium carbonate (1.29 g, 9.32 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 60° C. for 15 hours. 1 N hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine, the aqueous layer was separated by a phase separator, the resultant was concentrated at reduced pressure, and the resultant residue was purified by 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 minutes (analysis condition SMD-TFA05)

Reference 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

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The title compound was synthesized from 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-ene-9-carboxamide (Example 332) in a manner similar to that of Reference Example 106.

LCMS: m/z 764[M+H]⁺

HPLC retention time: 1.62 minutes (analysis condition 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

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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) were dissolved in N,N-dimethyl formamide (100 μL), then N-ethyl-N-isopropylpropan-2-amine (4.6 μL, 27.0 μmol) and tetrabutylammonium iodide (0.5 mg, 1.33 μmol) were added, and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was diluted with N,N-dimethyl formamide (0.5 mL) and purified by HPLC to obtain the title compound (8.0 mg, 78%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.31 minutes (analysis condition SMD-TFA05)

Examples 339 to 380

Various amines which were known from literature or commercialized were used, and operations similar to those of Example 338 were carried out to synthesize the compounds described in the following Table. Note that if the amine was hydrochloride, the amine was not directly used for the reaction and used for the reaction after hydriodic acid (57 wt. %, 2 equivalent weight) was allowed to act and the corresponding hydroiodide was formed.

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm, 100×30 mml.D., S-5 μm, 12 nm).

TABLE 32

LCMS
Retention

Example

analysis condition
time
m/z

No.
Structural formula
No.
(min)
[M + H]+

339

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SMD-TFA05
1.34
769

340

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SMD-TFA05
1.34
783

341

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SMD-TFA05
1.34
785

342

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SMD-TFA05
1.35
785

343

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SMD-TFA05
1.34
785

344

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SMD-TFA05
1.35
785

345

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SMD-TFA05
1.37
785

346

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SMD-TFA05
1.33
773

347

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SMD-TFA05
1.28
745

348

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SMD-TFA05
1.37
803

349

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SMD-TFA05
1.38
787

350

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SMD-TFA05
1.38
787

351

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SMD-TFA05
1.27
775

352

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SMD-TFA05
1.51
739

353

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SMD-TFA05
1.28
786

354

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SMD-TFA05
1.31
800

355

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SMD-TFA05
1.35
799

356

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SMD-TFA05
1.35
771

357

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SMD-TFA05
1.35
773

358

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SMD-TFA05
1.16
840

359

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SMD-TFA05
1.29
784

360

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SMD-TFA05
1.22
800

361

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SMD-TFA05
1.23
844

362

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SMD-TFA05
1.23
814

363

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SMD-TFA05
1.31
834

364

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SMD-TFA05
1.30
827

365

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SMD-TFA05
1.35
799

366

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SMD-TFA05
1.34
785

367

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SMD-TFA05
1.36
797

368

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SMD-TFA05
1.34
787

369

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SMD-TFA05
1.39
777

370

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SMD-TFA05
1.37
799

371

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SMD-TFA05
1.36
799

372

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SMD-TFA05
1.40
801

373

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SMD-TFA05
1.31
759

374

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SMD-TFA05
1.19
854

375

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SMD-TFA05
1.40
799

376

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SMD-TFA05
1.25
814

377

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SMD-TFA05
1.30
828

378

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SMD-TFA05
1.26
858

379

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SMD-TFA05
1.34
848

380

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SMD-TFA05
1.37
783

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

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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 minute. After the reaction mixture was concentrated at reduced pressure, methanol and toluene were added for azeotropic removal to obtain L-aspartate dimethyl ester hydroiodide as a crude product. The resultant hydroiodide of amine 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) (Reference Example 109) were dissolved in N,N-dimethyl formamide (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. After the reaction mixture was diluted with 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 resultant was purified by HPLC to obtain the title compound (71.5 mg, 61%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (100×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 817[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition SMD-TFA05)

Example 382
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]pentanedioate

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First Step

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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 (Reference Example 109) and diethyl 3-aminopentanedioate were used as reagents, and operations similar to those of Example 337 were carried out to synthesize 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]pentanedioate.

Second Step

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]pentanedioate (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 minutes. The reaction mixture was diluted with formic acid and water and purified by HPLC to obtain the title compound (32.4 mg, 72%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 831[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition 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

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First Step

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6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-5,6-diazaspiro[3.5]non-8-ene-8-carboxylic acid 2-methylpropyl ester (Reference Example 106) and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]aniline (Reference Example 13) were used as reagents, and operations similar to those of Third Step of Example 149 were carried out to synthesize 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.

Second Step

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(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) were 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. After a 1 N aqueous dipotassium hydrogenphosphate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated sodium bicarbonate solution and a brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate/hexane) to obtain 3-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]propyl methanesulfonate (316 mg, 75%).

LCMS: m/z 269[M+H]⁺

HPLC retention time: 0.77 minutes (analysis condition SMD-TFA05)

Third Step

6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrydin-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]propyl methanesulfonate (8.77 mg, 33.0 μmol) were dissolved in acetonitrile (117 μL), cesium carbonate (22.8 mg, 233 μmol) was added, and the mixture was stirred at 75° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, an aqueous hydrochloric acid solution (6N, 38.9 μL, 233 μmol) and methanol (38.9 μL) were added, and the mixture was stirred at room temperature for 1 hour. A 6 N aqueous sodium hydroxide solution was added to the reaction mixture, and after the mixture was filtered and concentrated, the resultant was diluted with N,N-dimethyl formamide (0.5 mL) and purified by HPLC to obtain the title compound (11.9 mg, 66%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (100×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 775[M+H]⁺

HPLC retention time: 1.40 minutes (analysis condition SMD-TFA05)

Examples 384 to 400

Bromide(2-[2-(3-bromopropoxy)ethoxy]oxane, 2-[2-(4-bromobutoxy)ethoxy]oxane, 2-[2-(5-bromopentoxy)ethoxy]oxane, 2-[3-(3-bromopropoxy)propoxy]oxane, 2-[3-(4-bromobutoxy)propoxy]oxane, 2-[3-(5-bromopentoxy)propoxy]oxane synthesized by a method similar to that of First Step of Example 147 by using alcohol(2-(oxan-2-yloxy)ethanol, 3-(oxan-2-yloxy)propan-1-ol), and dibromide (1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane) which were known from literature or commercialized, and 3-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]propyl methanesulfonate (Example 383), (S)-4-((4-bromobutoxy)methyl)-2,2-dimethyl-1,3-dioxolane (Reference Example 74), and (S)-4-(((5-bromopentyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane (Reference Example 78), 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrydin-3-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide synthesized by a method similar to that of First Step of Example 383 by using 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid 2-methylpropyl ester (Example 332) and 4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrydin-3-yl]aniline (Reference Example 13), 6-[(2,3-difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrydin-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 (Reference 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-ene-9-carboxamide (Example 332) were used, and operations similar to those of Example 383 were carried out to synthesize the compounds described in the following Table.

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm, 100×30 mml.D., S-5 μm, 12 nm)

TABLE 33

Ex-

LCMS
Reten-

am-

analysis
tion
m/z

ple

condition
time
[M +

No.
Structural formula
No.
(min)
H]+

384

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SMD-TFA05
1.51
789

385

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SMD-TFA05
1.54
803

386

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SMD-TFA05
1.43
789

387

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SMD-TFA05
1.54
803

388

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SMD-TFA05
1.57
817

389

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SMD-TFA05
1.50
776

390

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SMD-TFA05
1.52
790

391

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SMD-TFA05
1.55
804

392

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SMD-TFA05
1.52
790

393

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SMD-TFA05
1.55
804

394

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SMD-TFA05
1.58
818

395

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SMD-TFA05
1.63
760

396

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SMD-TFA05
1.65
774

397

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SMD-TFA05
1.68
788

398

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SMD-TFA05
1.66
774

399

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SMD-TFA05
1.68
788

400

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SMD-TFA05
1.57
802

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

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The title 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 (Reference Example 107) and 1-bromo-2-(2-methoxyethoxy)ethane in a manner similar to that of Third Step of Reference Example 383.

LCMS: m/z 746[M+H]⁺

HPLC retention time: 1.66 minutes (analysis condition 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-ene-8-carboxamide

First Step

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6-(4-(2-Bromoethoxy)-2,3-difluorobenzyl)-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, 0.013 mmol) (Reference Example 108) was dissolved in 1,3-dimethyl-2-imidazolidinone (100 μL), and then a 2.0 M methylamine-tetrahydrofuran solution (400 μL, 0.800 mmol), N,N-diisopropyl ethylamine (4.6 μL, 0.027 mmol), then tetrabutyl ammonium iodide (0.5 mg, 0.001 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was concentrated at reduced pressure, a 0.5 M hydrochloric acid-methanol solution (80 μL, 0.040 mmol) was added, and normal butanol and toluene were 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 minutes (analysis condition SMD-TFA05)

Second Step

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The crude product of 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 (6.25 μL, 0.104 mmol), triacetoxy sodium borohydride (16.5 mg, 0.078 mmol), and acetic acid (10 μL, 0.175 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Oxetan-3-one (6.25 μL, 0.104 mmol) and triacetoxy sodium borohydride (16.5 mg, 0.078 mmol) were further added, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated and diluted with N,N-dimethyl formamide, the resultant was purified by HPLC to obtain the title compound (3.8 mg, two-step yield of 39%).

LCMS: m/z 757[M+H]⁺

HPLC retention time: 1.25 minutes (analysis condition 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-ene-8-carboxamide

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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 (Reference Example 107) was dissolved in acetonitrile (200 μL), then oxetan-3-yl 4-methylbenzenesulfonate (14.2 mg, 0.062 mmol) and cesium carbonate (30.4 mg, 0.093 mmol) were added, and the mixture was stirred at 80° C. overnight. After the reaction mixture was diluted with N,N-dimethyl formamide and water, the resultant was purified by HPLC to obtain the title compound (14.1 mg, 65%).

LCMS: m/z 700[M+H]⁺

HPLC retention time: 1.62 minutes (analysis condition 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

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First Step

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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 (Reference Example 107) (100 mg, 0.16 mmol) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (62.6 mg, 0.31 mmol) were dissolved in tetrahydrofuran (311 μL), then N,N,N′,N′-tetramethylazodicarboxamide (53.5 mg, 0.31 mmol) was added, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated at reduced pressure, and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain 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 minutes (analysis condition SMD-TFA05)

Second Step

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Hydrochloric acid (a 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-en-6-yl]methyl]phenoxy]methyl]pyrrolidine-1-carboxylate (104 mg, 0.13 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated at reduced pressure, toluene was added for azeotropic removal to obtain (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 minutes (analysis condition SMD-TFA05)

Third Step

(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) were dissolved in N,N-dimethyl formamide (100 μL), then N-ethyl-N-isopropylpropan-2-amine (6.9 μL, 39.0 μmol) and tetrabutylammonium iodide (0.5 mg, 1.31 μmol) were added, and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was diluted with N,N-dimethyl formamide (0.5 mL) and purified by HPLC to obtain the title compound (3.2 mg, 31%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 785[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition 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

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The title 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 (Reference Example 107) and (S)-tert-butyl 3-hydroxy pyrrolidine-1-carboxylate in a manner similar to that of First to Third Steps of Example 404.

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.30 minutes (analysis condition 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

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The title 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 (Reference Example 107) and tert-butyl 3-hydroxyazetidine-1-carboxylate in a manner similar to that of First to Third Steps of Example 404.

LCMS: m/z 756[M+H]⁺

HPLC retention time: 1.33 minutes (analysis condition 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

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A tetrahydrofuran solution (1M) (0.109 mL, 0.109 mmol) of trimethylphosphine was added for as long as 30 seconds 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) in a state in which they were heated at 60° C. The reaction mixture was stirred at 60° C. for 16 hours. After the reaction mixture was cooled to room temperature, the resultant was blown with nitrogen to remove the solvent. The residue was dissolved in dimethylformamide and formic acid, and the resultant was purified by HPLC (0.1% formic acid water/0.1% formic acid acetonitrile) to obtain the title compound (4.3 mg, 34%).

LCMS: m/z 785[M+H]⁺

HPLC retention time: 1.30 minutes (SMD-TFA05)

Examples 408 to 411

Appropriate alkyl alcohols were used, and operations similar to those of Example 407 were carried out to synthesize the compounds described in the following Table.

TABLE 34

LCMS

Example

Analysis
Retention time
m/z

No.
Structural formula
condition
(min)
[M + H]⁺

408

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SMD-TFA05
1.30
771

409

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SMD-TFA05
1.31
742

410

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SMD-TFA05
1.33
756

411

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SMD-TFA05
1.30
741

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 Step

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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) (Reference Example 109) was used, and operations similar to those of First Step of Example 402 were carried out to obtain a crude product of 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 minutes (analysis condition SMD-TFA05)

Second Step

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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 was used, and operations similar to those of Second Step of Example 402 were carried out to obtain the title compound (11.3 mg, two-step yield of 56%).

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.19 minutes (analysis condition SMD-TFA05)

¹H-NMR (DMSO-D₆) 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
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

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The title 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 (Reference Example 107) and 2-(chloromethyl)tetrahydrofuran in a manner similar to that of Third Step of Example 383.

LCMS: m/z 742[M+H]⁺

HPLC retention time: 1.61 minutes (analysis condition 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

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The title 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 by a method similar to that of Example 407.

LCMS: m/z 771[M+H]⁺

HPLC retention time: 1.25 minutes (analysis condition SQD-FA05)

¹H-NMR (CDCl₃) 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)pyrimidin-4-yl)phenyl)carbamoyl)-6,7-diazaspiro[4.5]dec-9-en-7-yl)methyl)phenoxy)ethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium formate

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First Step

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A solution of 7-[(2,3-difluoro-4-hydroxyphenyl)methyl]-10-hydroxy-6-methyl-8-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylic acid 2-methylpropyl ester, 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-dimethyl formamide (1.01 mL) was heated at 60° C. for 18 hours. The residue was dissolved in N,N-dimethyl formamide and formic acid, and the reaction mixture was purified by C-18 reverse-phase column chromatography 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 minutes (SMD-TFA05)

Second Step

A solution of 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 (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. After the reaction mixture was cooled to room temperature, the resultant was blown with nitrogen gas to remove the solvent. The residue was dissolved in N,N-dimethyl formamide and formic acid, and the resultant was purified by HPLC (0.1% formic acid water/0.1% formic acid acetonitrile) to obtain the title compound (78 mg, 73%).

LCMS: m/z 796[M]⁺

HPLC retention time: 1.05 minutes (analysis condition SQD-FA05)

Example 416
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

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First Step

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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 2-methylpropyl ester was synthesized from methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate hydrochloride (Reference Example 105) in a manner similar to that of Fourth Step of Example 237.

LCMS: m/z 540[M+H]⁺

HPLC retention time: 1.11 minutes (analysis condition SMD-TFA05)

Second Step

The title compound was synthesized from 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 2-methylpropyl ester and 2-(5-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-4-(trifluoromethyl)aniline (Reference Example 96) in a manner similar to that of Fifth Step of Example 237.

LCMS: m/z 787[M+H]⁺

HPLC retention time: 1.41 minutes (analysis condition 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

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First Step

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2,3-Difluoro-4-iodobenzaldehyde and methyl 1-(methylamino)cyclopentane carboxylate hydrochloride were used, and operations similar to those of Third to Fifth Steps of Example 13 were carried out to synthesize the title compound (2.69 g, three-step yield of 69%).

LCMS: m/z 768[M+H]⁺

HPLC retention time: 0.99 minutes (analysis condition SQD-FA50)

Second Step

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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 (I) 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 nitrogen atmosphere at 90° C. for 5 hours. Aqueous ammonia 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 obtain the title compound (210 mg, 95%).

LCMS: m/z 772[M+H]⁺

HPLC retention time: 0.83 minutes (analysis condition SQD-FA05)

Example 418
7-[[2,3-Difluoro-4-[4-[methyl-[(2 S,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

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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-dimethyl formamide (1 mL), then (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol (31.5 mg, 0.161 mmol), HATU (40.9 mg, 0.108 mmol), and N-ethyl-N-isopropylpropan-2-amine (20.86 mg, 0.161 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture (0.2 mL), and the resultant was purified by C18 reverse-phase column 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 minutes (analysis condition 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

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First Step

2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate

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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 chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the title compound (620 mg, 79%) as a white plate-like crystal.

LCMS: m/z 415[M+H]⁺

HPLC retention time: 0.88 minutes (analysis condition SQD-FA05)

Second Step

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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 (100 mg, 0.152 mmol) was dissolved in acetonitrile (5 mL), then oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) obtained in First Step (252 mg, 0.61 mmol) and cesium carbonate (49.6 mg, 0.152 mmol) were added, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was purified by C18 reverse-phase column 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 minutes (analysis condition SQD-FA05)

Third Step

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 obtained in Second Step (30 mg, 0.033 mmol) and 3-aminopropane-1,2-diol (9.11 mg, 0.1 mmol) were dissolved in acetonitrile (1 mL), and the mixture was stirred at 50° C. for 5 hours. The reaction 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 819[M+H]⁺

HPLC retention time: 0.82 minutes (analysis condition 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

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(2R,3R,4R,5S)-6-(Methylamino)hexane-1,2,3,4,5-pentol was used as a raw material, and operations similar to those of Example 419 were carried out to synthesize the title compound.

LCMS: m/z 923[M+H]⁺

HPLC retention time: 0.79 minutes (analysis condition SQD-FA05)

Example 421
7-[[2,3-Difluoro-4-[2-[2-[2-[2-[2-[methyl-[(2R,3 S,4S,5 S)-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)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide

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2-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol was used as a raw material, and operations similar to those of Example 419 were carried out to synthesize the title compound.

LCMS: m/z 1055[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition 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

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First Step

tert-Butyl 3-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]propanoate

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2-[2-(2-Hydroxyethoxy)ethoxy]ethanol (2 g, 13.3 mmol) was dissolved in THF (5 mL), and NaH (8 mg, 0.2 mol) was added. After the mixture was stirred at room temperature for 10 minutes, tert-butyl prop-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 resultant residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the target title compound (488 mg, 45%) as colorless clear oil.

¹H-NMR (CDCl₃) 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 Step

tert-Butyl 3-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]propanoate

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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 the mixture was stirred at room temperature for 17 hours, the reaction mixture was concentrated, and the resultant residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain the title compound (550 mg, 73%) as colorless clear oil.

LCMS: m/z 450[M+H₂O]⁺

HPLC retention time: 0.90 minutes (analysis condition SQD-FA05)

Third Step

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After tert-butyl 3-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]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) were dissolved in acetonitrile (2 mL), cesium carbonate (117 mg, 1.36 mol) was added, and the mixture was stirred at 70° C. for 2 hours. After water (0.1 mL) was added to the reaction mixture, the resultant 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 minutes (analysis condition SQD-FA05)

Fourth Step

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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 the reaction mixture was stirred at room temperature for 2 hours, the resultant was concentrated to distill TFA away. The resultant residue was directly used for the next reaction.

LCMS: m/z 818[M+H]⁺

HPLC retention time: 1.15 minutes (analysis condition SQD-FA05)

Fifth Step

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 (40 mg, 0.05 mmol), 3-aminopropane-1,2-diol (9 mg, 0.1 mol), and HATU (37.2 mg, 0.1 mol) were dissolved in DMF (1 mL), then diisopropylethylamine (12.6 mg, 0.1 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (0.1 mL) was added to the reaction mixture, and the resultant was purified by C18 reverse-phase column chromatography to obtain the title compound (18 mg, 41%) as a white amorphous solid.

LCMS: m/z 995[M+H]⁺

HPLC retention time: 1.01 minutes (analysis condition SQD-FA05)

Examples 423 and 424

The compounds described in the following Table were synthesized by carrying out Steps similar to those of Example 422 by using 2-[2-(2-hydroxyethoxy)ethoxy]ethanol as a starting material.

TABLE 35

Ex-

am-

ple

No.
Structural formula

423

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424

LCMS
Retention

Example
Analysis
time
m/z

No.
condition
(min)
[M + H]⁺

423
SQD-FA05
1.02
1039

424
SQD-FA05
1.06
935

Examples 425 and 426

The compounds described in the following Table were synthesized by carrying out Steps similar to those of Example 422 by using 2-[2-hydroxyethyl(methyl)amino]ethanol as a starting material.

TABLE 36

Ex-

am-

ple

No.
Structural formula

425

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426

LCMS
Retention

Example
Analysis
time
m/z

No.
condition
(min)
[M + H]⁺

425
SQD-FA05
0.77
1008

426
SQD-FA05
0.78
904

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

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First Step

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After 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 the mixture was stirred at room temperature for 5 hours, the resultant was concentrated, and the residue was purified by C18 reverse-phase column chromatography to obtain the title compound (28 mg, 74%) as a white amorphous solid.

LCMS: m/z 845[M+H]⁺

HPLC retention time: 1.25 minutes (analysis condition SQD-FA05)

Second Step

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

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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 4N—HCl ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the resultant residue was used for the next reaction without purification.

LCMS: m/z 745[M+H]⁺

HPLC retention time: 0.81 minutes (analysis condition SQD-FA05)

Third Step

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) were dissolved in methanol (1 mL), and the resultant was stirred in a sealed tube at 70° C. for 20 hours. Water (0.1 mL) was added to the reaction mixture, and the resultant 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 minute (analysis condition 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

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The title compound was synthesized by carrying out Steps similar to those of Example 427 by using tert-butyl N-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate as a starting material.

LCMS: m/z 1011[M+H]⁺

HPLC retention time: 1.01 minutes (analysis condition 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

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First Step

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2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (79 mg, 0.192 mmol) and cesium carbonate (15.6 mg, 0.048 mmol) were 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 (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 the reaction was completed, the reaction mixture was neutralized with formic acid, and the reaction mixture was purified by C18 reverse-phase column chromatography to obtain 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 minutes (analysis condition SMD-TFA05)

Second Step

2-Methoxy-N-methyl ethanamine (0.043 mL, 0.399 mmol) was added to a 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 the reaction was completed, the reaction mixture was purified by C18 reverse-phase column chromatography to obtain the title compound (22.3 mg, 68%).

LCMS: m/z 817[M+H]⁺

HPLC retention time: 1.43 minutes (analysis condition SMD-TFA05)

Examples 430 to 434

Appropriate alkylating agents and commercial amines were used to synthesize the compounds described in the following Table by carrying out operations similar to those of Example 429.

TABLE 37

Ex

am-

ple

No.
Structural formula

430

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431

432

433

434

LCMS
Retention

Analysis
time
m/z

Example No.
condition
(min)
[M + H]⁺

430
SMD-TFA05
1.45
861

431
SMD-TFA05
1.46
905

432
SMD-TFA05
1.46
949

433
SQD-FA05
0.79
923

434
SQD-FA05
0.81
1055

Example 435
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-methyl]phenoxy]ethylamino]ethanesulfonic acid

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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) (Reference Example 109) was dissolved in N,N-dimethyl formamide (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. After the reaction mixture was diluted with formic acid and water and filtered, the resultant was purified by HPLC to obtain the title compound (8.0 mg, 38%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 809.1[M+H]⁺

HPLC retention time: 1.32 minutes (analysis condition SMD-TFA05)

Example 436
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 ethanesulfonic acid

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First Step

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(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 (Reference Example 109) and (R)-2-amino-3-methoxy-3-oxopropane-1-sulfonic acid hydrochloride in a manner similar to that of Example 381.

LCMS: m/z 867.0[M+H]⁺

HPLC retention time: 1.37 minutes (analysis condition SMD-TFA05)

Second Step

The title 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 in a manner similar to that of Reference Example 381.

LCMS: m/z 853.0[M+H]⁺

HPLC retention time: 1.31 minutes (analysis condition SMD-TFA05)

Reference Example 110
2-Chloro-N-(2-methoxyethyl)-N-methylethanamine hydrochloride

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First Step

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 resultant was filtered and concentrated at reduced pressure to obtain 2-((2-methoxyethyl)(methyl)amino)ethanol (16.5 g) as a crude product.

Second Step

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 at reduced pressure to obtain the title compound (20.5 g, 88%).

¹H-NMR (DMSO-D₆) 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

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First Step

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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 (Reference Example 107) (500 mg, 0.76 mmol) was dissolved in N,N-dimethyl formamide (2.54 mL), then N-iodosuccinimide (222 mg, 0.99 mmol) was added, 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 obtain 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 (569 mg, 96%).

LCMS: m/z 784.1[M+H]⁺

HPLC retention time: 1.67 minutes (analysis condition SMD-TFA05)

Second Step

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 nitrogen atmosphere at 65° C. for 1.5 hours. An aqueous formic acid solution was added to the reaction mixture, and the resultant was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain the title compound (341 mg, 87%).

LCMS: m/z 899.2[M+H]⁺

HPLC retention time: 1.46 minutes (analysis condition SMD-TFA05)

Example 438
7-[[2,3-Difluoro-4-[2-[2-methoxyethyl(methylamino]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

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First Step

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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), a tris(dibenzylideneacetone)dipalladium chloroform complex (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-dimethyl formamide (1.04 mL), then acetic anhydride (58.5 μL, 0.62 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 85° C. for 30 minutes. N,N-dimethyl formamide and methanol were added to the reaction mixture, and the resultant was purified by C18 reverse-phase column chromatography (acetonitrile/water) to obtain 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 minutes (analysis condition SMD-TFA05)

Second Step

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-dimethyl formamide (100 μL), and the mixture was stirred under nitrogen atmosphere at 40° C. for 2 hours. An aqueous formic acid solution was added to the reaction mixture, and the resultant was purified by HPLC to obtain the title compound (8.0 mg, 38%).

Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 μm, 12 nm)

LCMS: m/z 902.1 [M+H]⁺

HPLC retention time: 1.17 minutes (analysis condition SMD-FA05)

Reference Example 111
5-(2-Methoxyethoxy)-2-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)aniline

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First Step

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2-Iodo-5-(2-methoxyethoxy)-4-(trifluoromethyl)aniline (1.30 g, 3.60 mmol) (Reference 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 nitrogen atmosphere at 110° C. for 4 hours. Ethyl acetate was added to the reaction mixture, the mixture was filtered, the resultant was concentrated at reduced pressure, and the resultant residue was purified by C18 reverse-phase column chromatography (acetonitrile/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 minutes (analysis condition SQD-FA05)

Second Step

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 (Reference Example 91) (199 mg, 1.01 mmol), a 1,1′-bis(diphenylphosphino)ferrocene-palladium (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 nitrogen atmosphere at 90° C. for 1 hour. Water was added to the reaction mixture, and the resultant was extracted with ethyl acetate. The organic layer was washed with water and a brine, the aqueous layer was separated by a phase separator, the resultant was concentrated at reduced pressure, and the resultant residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to obtain the title compound (180 mg, 90%).

LCMS: m/z 396.1[M+H]⁺

HPLC retention time: 1.24 minutes (analysis condition SMD-TFA05)

Reference Example 112
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 2-methylpropyl ester

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Methyl 1-[[(E)-[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methylideneamino]-methylamino]cyclopentane-1-carboxylate hydrochloride (Reference Example 105) was used, and operations similar to those of Fourth Step of Example 237 were carried out to synthesize the title compound.

LCMS: m/z 540.2[M+H]⁺

HPLC retention time: 1.11 minutes (analysis condition 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

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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 2-methylpropyl ester and 5-(2-methoxyethoxy)-2-[5-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-(trifluoromethyl)aniline were used, and operations similar to those of Fifth Step of Example 237 were carried out to synthesize the title compound.

LCMS: m/z 861.4[M+H]⁺

HPLC retention time: 1.40 minutes (analysis condition 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

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Purification condition: HPLC

Mobile phase: MeCN/water (0.1% formic acid)

Column: YMC-Actus Triart C18 (50×30 mml.D., S-5 m, 12 nm)

LCMS: m/z 850[M+H]⁺

HPLC retention time: 1.26 minutes (analysis condition 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-ene-9-carboxamide

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The title compound was synthesized by carrying out Steps and operations similar to those of Example 422 by using 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol and tert-butyl 2-bromoacetate as a starting material.

LCMS: m/z 1069[M+H]⁺

HPLC retention time: 1.00 minute (analysis condition SQD-FA05)

Examples 442 to 445

The aniline compound of Example 417 and appropriate aldehydes or ketones were used, and the following operations were carried out to synthesize the compounds described in the following Table.

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 18 M sulfuric acid of an amount equivalent to one-fifth of the amount of tetrohydrofuran was added at 0° C. Subsequently, sodium tetrahydroborate was added in three batches, and the mixture was stirred at 0° C. or at room temperature for 3 hours and more. Triethylamine, water, and dimethylsulfoxide were added to the reaction mixture, and the resultant solution was purified by C18 reverse-phase column chromatography to synthesize the compounds of the Examples described in the following Table.

TABLE 38

LCMS
Retention

Example

analysis condition
time
m/z

No.
Structural formula
No.
(min)
[M + H]⁺

442

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SQD-AA05
1.21
786

443

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SQD-AA05
1.22
800

444

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SQD-AA05
1.24
814

445

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SQD-AA05
1.23
814

Examples 446 and 447

The appropriate iodide derivative of Example 417, 3-morpholinopropan-1-amine, and 2-morpholinoethanamine were used, and operations similar to those of Example 417 were carried out to synthesize the compounds described in the following Table.

TABLE 39

LCMS
Retention

Example

analysis condition
time
m/z

No.
Structural formula
No.
(min)
[M + H]⁺

446

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SQD-AA50
0.88
784

447

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SQD-AA50
0.87
770

Reference Example 113
Methyl 1-((methylamino)cyclopentanecarboxylate 4-toluenesulfonate

First Step

Methyl 1-((tert-butoxycarbonyl)amino)cyclopentane carboxylate

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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 at reduced pressure, and water (6.00 mL) and triethylamine (7.55 mL, 54.3 mmol) were added to the resultant residue. Di-tert-butyl dicarbonate (3.95 g, 18.1 mmol) and tert-butyl methyl ester (24.0 mL) were added to this solution, and the mixture was stirred at 50° C. for 1 hour. The aqueous layer was separated, tetrahydrofuran (9.00 mL) was added to the organic layer, and the resultant was concentrated at reduced pressure. Tetrahydrofuran (15.0 mL) was added to the resultant residue, and the resultant was concentrated at reduced pressure to obtain the title compound as pale yellow oil.

¹H-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 Step

Methyl 1-((tert-butoxycarbonyl)methylamino)cyclopentanecarboxylate

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Methyl 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylate obtained in First Step was dissolved in 1-methyl 2-pyrrolidinone (24.0 mL), then sodium hydroxide (1.45 g, 36.2 mmol) and methyl iodide (3.38 mL, 54.3 mmol) were added, 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 resultant was extracted with isopropyl acetate (15.0 mL) twice. The resultant organic layer was washed serially with a 10% aqueous sodium thiosulfate solution (15.0 mL) and a 10% aqueous sodium chloride solution (15.0 mL). The resultant organic layer was concentrated at reduced pressure to obtain the title compound (5.88 g, 83%).

¹H-NMR (DMSO-D₆) 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 Step

Methyl 1-(methylamino)cyclopentanecarboxylate 4-toluenesulfonate

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The title compound was synthesized from 1-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid in a manner similar to that of Reference Examples 87 and 88.

Reference Example 114
2,3-Difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]benzaldehyde hydrochloride

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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 generated crystal was filtered and dried at reduced pressure to obtain the title compound (68 mg, 30%).

¹H-NMR (DMSO-D₆) 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 Test

Test Example 1: Inhibitory Effect on ³³PO₄Uptake into Rat Small-Intestinal Brush Border Membrane Vesicles

Brush border membrane vesicles (BBMVs) were prepared using the upper region of the small intestine of each Wistar female rat (4-5 weeks old). The preparation of BBMVs was performed 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 January; 9 (1): 143-50). The ³³PO₄transport activity of the small-intestinal BBMVs was determined by the rapid 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 ³³PO₄, or DMSO 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 seconds. Then, ice-cold buffer C (110 mM NaCl, 1 mM KH₂PO₄, and 10 mM HEPES (pH 7.5)) was added to each reaction mixture, which was immediately suction-filtered through a Millipore filter. The filter was washed with buffer C, and each sample was then dissolved in a liquid scintillator. The amount of ³³PO₄uptake into BBMVs was measured using a liquid scintillation counter. The rate of inhibition was determined according to the following expression:

Rate (%) of inhibition=(1−(Amount of ³³PO₄uptake into the test compound-supplemented and buffer A-treated BBMVs−Amount of ³³PO₄uptake into the DMSO-supplemented and buffer B-treated BBMVs)/(Amount of ³³PO₄uptake into the DMSO-supplemented and buffer A-treated BBMVs−Amount of ³³PO₄uptake into the DMSO-supplemented and buffer B-treated BBMVs))×100

The rate of inhibition of ³³PO₄uptake into the rat small-intestinal brush border membrane vesicles by 1 μM of the test compound (the rate of uptake inhibition) is shown in Tables 40-1 to 40-8.

TABLE 40-1

Rate of uptake

Example No.
inhibition (%) (1 μM)

1
28

2
19

3
11

4
32

5
54

6
48

7
69

8
37

9
63

10
37

11
22

12
27

13
58

14
29

15
42

16
38

17
33

18
12

19
41

20
21

21
61

22
50

23
84

24
76

25
82

26
72

27
76

28
72

29
75

30
71

31
76

32
73

33
77

34
99

35
79

36
80

37
89

38
90

39
90

40
87

41
84

42
67

43
79

44
94

45
73

46
71

47
91

48
87

49
85

50
79

51
72

52
57

53
72

54
72

55
85

56
88

57
71

58
46

59
84

60
78

61
71

62
73

TABLE 40-2

Rate of uptake

Example No.
inhibition (%) (1 μM)

63
72

64
77

65
98

66
96

67
91

68
84

69
74

70
79

71
97

72
92

73
74

74
82

75
74

76
77

77
80

78
71

79
71

80
75

81
74

82
100

83
90

84
91

85
71

86
83

87
84

88
39

89
67

90
91

91
87

92
81

93
56

94
73

95
80

96
83

97
89

98
53

99
82

100
69

101
57

102
65

103
78

104
73

105
72

106
79

107
54

108
54

109
52

110
57

111
56

112
43

113
84

114
86

115
85

116
72

117
78

118
81

119
71

120
66

121
72

122
82

123
87

124
81

TABLE 40-3

Rate of uptake

Example No.
inhibition (%) (1 μM)

125
76

126
71

127
95

128
72

129
63

130
72

131
87

132
71

133
83

134
94

135
90

136
80

137
92

138
93

139
88

140
77

141
83

142
76

143
71

144
72

145
78

146
71

147
57

148
75

149
80

150
87

151
92

152
54

153
73

154
73

155
77

156
59

157
89

158
84

159
89

160
77

161
94

162
73

163
79

164
64

165
75

166
73

167
73

168
72

169
73

170
73

171
78

172
72

173
73

174
87

175
85

176
75

177
85

178
81

179
83

180
75

181
85

182
86

183
82

184
79

185
83

186
88

TABLE 40-4

Rate of uptake

Example No.
inhibition (%) (1 μM)

187
80

188
93

189
73

190
84

191
87

192
88

193
82

194
80

195
76

196
90

197
82

198
75

199
79

200
80

201
77

202
75

203
91

204
87

205
86

206
76

207
73

208
90

209
76

210
71

211
72

212
98

213
79

214
91

215
86

216
76

217
83

218
82

219
95

220
96

221
82

222
97

223
77

224
74

225
76

226
71

227
82

228
77

229
73

230
75

231
80

232
79

233
75

234
73

235
65

236
60

237
51

238
47

239
48

240
72

241
86

242
69

243
63

244
71

245
40

246
52

247
51

248
45

TABLE 40-5

Rate of uptake

Example No.
inhibition (%) (1 μM)

249
50

250
52

251
43

252
53

253
40

254
58

255
80

256
79

257
71

258
87

259
52

260
70

261
77

262
43

263
66

264
48

265
52

266
62

267
71

268
63

269
80

270
75

271
60

272
43

273
41

274
43

275
42

276
68

277
41

278
69

279
53

280
50

281
41

282
55

283
45

284
46

285
62

286
50

287
47

288
61

289
55

290
59

291
47

292
44

293
47

294
40

295
21

296
17

297
36

298
10

299
45

300
74

301
79

302
79

303
42

304
51

305
66

306
58

307
41

308
63

309
68

310
63

TABLE 40-6

Rate of uptake

Example No.
inhibition (%) (1 μM)

311
65

312
74

313
65

314
72

315
63

316
64

317
57

318
43

332
3

333
29

334
22

335
30

336
44

337
47

338
66

339
66

340
63

341
64

342
43

343
68

344
58

345
73

346
42

347
28

348
31

349
55

350
45

351
22

352
27

353
26

354
31

355
36

356
58

357
45

358
34

359
37

360
21

361
20

362
17

363
11

364
36

365
34

366
38

367
43

368
26

369
43

370
41

371
38

372
38

373
27

374
42

375
31

376
33

377
29

378
35

379
37

380
43

381
28

382
21

383
26

TABLE 40-7

Rate of uptake

Example No.
inhibition (%) (1 μM)

384
39

385
39

386
36

387
23

388
15

389
29

390
58

391
42

392
47

393
45

394
45

395
39

396
38

397
40

398
34

399
42

400
36

401
39

402
54

403
71

404
43

405
30

406
27

407
30

408
47

409
43

410
49

411
32

412
52

413
34

414
27

415
21

416
50

417
48

418
29

419
22

420
19

421
24

422
29

423
5

424
17

425
5

426
24

427
12

428
14

429
41

430
29

431
26

432
11

433
19

434
24

435
11

436
12

437
45

438
33

439
35

440
28

441
22

442
24

443
28

TABLE 40-8

Rate of uptake

Example No.
inhibition (%) (1 μM)

444
24

445
29

446
31

447
50

Test Example 2: Inhibitory Effect on PO₄Uptake into Human NaPi-IIb-Expressing Cell

CHO cells were transfected with human NaPi-IIb expression plasmids, and a stably human NaPi-IIb-expressing cell line was obtained using G418. The human NaPi-IIb-expressing cells were inoculated to a 96-well plate and incubated overnight in a CO₂incubator. 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 KCl, 1 mM CaCl₂, 0.5 mM MgCl₂, 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 buffer A supplemented with DMSO. After a given time, a 1/20 volume of buffer A containing ³³PO₄was added thereto and reacted at room temperature. After washing with ice-cold buffer A, a liquid scintillator was added to each reaction mixture, and the amount of ³³PO₄uptake was measured using TopCount. The rate of inhibition was determined according to the following expression:

Rate (%) of inhibition=(1−(Amount of ³³PO₄uptake in the test compound-supplemented and buffer B-treated well−Amount of ³³PO₄uptake in the DMSO-supplemented and buffer A-treated well)/(Amount of ³³PO₄uptake in the DMSO-supplemented and buffer B-treated well−Amount of ³³PO₄uptake in the DMSO-supplemented and buffer A-treated well))×100

IC₅₀values (μM) were calculated from a straight line joining two points intersecting the 50% rate of inhibition. The IC₅₀values of some compounds against ³³PO₄uptake into the human NaPi-IIb-expressing cells are shown in Tables 41-1 to 41-7.

TABLE 41-1

Example No.
IC50 (μM)

13
7.3

14
8.9

21
2.8

22
7.9

23
6.9

24
8.1

25
10.1

26
2.2

27
9.0

28
4.1

29
2.0

30
2.3

31
3.3

32
2.8

33
6.0

34
7.0

35
12.6

36
6.1

37
3.7

38
6.7

39
8.5

40
6.5

41
6.6

42
5.0

43
8.3

44
30.0

45
13.0

46
14.1

47
7.1

48
16.3

49
12.9

50
8.3

51
16.0

52
16.8

53
9.5

54
2.3

55
15.3

56
7.2

57
10.3

58
30.0

59
7.4

60
8.8

61
5.6

62
6.4

63
8.7

64
6.5

65
16.2

66
17.3

67
2.0

68
2.6

69
8.9

70
8.4

71
7.8

72
8.3

73
2.3

74
4.1

76
6.6

77
8.9

78
5.2

79
6.7

80
12.5

81
17.5

82
11.1

83
10.6

TABLE 41-2

Example No.
IC50 (μM)

84
7.9

85
6.2

86
5.3

87
8.3

89
4.8

90
2.4

91
15.7

92
20.2

93
17.4

94
8.8

95
5.4

96
2.8

97
2.7

98
10.6

99
4.3

100
6.7

101
9.4

102
10.9

103
11.0

104
10.8

105
6.3

106
12.0

107
25.9

108
26.1

109
9.4

110
19.8

111
20.0

112
30.0

113
15.5

114
7.9

115
6.9

116
8.1

117
9.5

118
9.1

119
9.2

120
20.5

121
16.0

122
8.6

123
14.8

124
2.5

125
1.3

126
5.5

127
17.6

128
12.0

129
13.7

130
8.9

131
15.3

132
5.0

133
13.1

134
19.7

135
12.3

136
17.6

137
19.7

138
11.9

139
17.0

140
16.2

141
7.8

142
17.6

143
6.7

144
2.1

145
7.1

146
10.2

TABLE 41-3

Example No.
IC50 (μM)

147
21.5

148
8.5

149
19.7

150
9.0

151
8.4

152
20.6

153
6.2

154
2.5

155
2.3

156
3.2

157
19.1

158
12.8

159
11.4

160
7.3

161
11.5

162
15.1

163
6.8

164
5.0

165
1.8

166
10.5

167
4.3

168
2.6

169
2.6

170
2.2

171
2.2

172
2.4

173
1.9

174
2.2

175
3.4

176
4.0

177
11.1

178
8.2

179
18.9

180
5.7

181
4.8

182
5.1

183
9.1

184
3.1

185
4.9

186
5.5

187
6.7

188
6.1

189
5.5

190
5.1

191
14.5

192
16.5

193
6.4

194
19.3

195
4.6

196
2.8

197
7.0

198
2.4

199
1.8

200
1.3

201
1.3

202
6.1

203
2.0

204
1.0

205
1.6

206
2.0

207
6.5

208
6.6

TABLE 41-4

Example No.
IC50 (μM)

209
4.8

210
1.7

211
5.7

212
2.9

213
6.4

214
7.0

215
6.2

216
8.0

217
4.7

218
7.2

219
4.2

220
12.2

221
6.6

222
17.6

223
17.9

224
7.2

225
5.1

226
3.1

227
3.7

228
5.7

229
1.5

230
2.1

231
5.6

232
4.2

233
2.3

234
9.4

235
4.8

236
24.7

237
12.8

238
8.5

239
8.5

240
9.1

241
16.5

242
7.8

243
7.4

244
7.3

245
7.7

246
8.6

247
8.2

248
17.6

249
9.8

250
17.9

251
7.6

252
9.5

253
4.4

254
9.7

255
9.8

256
4.4

257
6.0

258
2.7

259
10.0

260
6.4

261
7.7

262
9.9

263
3.0

264
19.4

265
13.3

266
11.6

267
7.5

268
7.4

269
4.5

270
14.6

TABLE 41-5

Example No.
IC₅₀(μM)

271
17.3

272
19.5

273
13.2

274
17.0

275
16.8

276
15.8

277
17.8

278
6.6

279
18.7

280
11.9

281
18.8

282
11.1

283
17.7

284
7.8

285
8.5

286
15.8

287
8.0

288
11.0

289
16.3

290
7.0

291
14.7

292
18.4

293
10.7

294
13.4

295
17.0

296
10.0

297
18.3

298
>30

299
18.8

300
9.3

301
2.6

302
7.8

303
16.0

304
3.5

305
5.9

306
8.4

307
4.6

308
12.6

309
6.5

310
4.7

311
8.2

312
6.3

313
18.3

314
11.8

315
9.8

316
14.2

317
9.6

318
8.6

332
23.9

333
19.5

334
10.3

335
8.7

336
19.7

337
17.0

338
13.4

339
19.1

340
10.0

341
7.6

342
8.8

343
21.0

344
13.7

345
7.7

346
6.9

347
25.2

TABLE 41-6

Example No.
IC₅₀(μM)

348
26.1

349
8.3

350
16.9

351
25.5

352
16.7

353
23.9

354
26.0

355
15.0

356
21.9

357
21.8

358
9.2

359
18.4

360
23.1

361
20.2

362
18.8

363
28.0

364
20.9

365
12.2

366
16.3

367
14.0

368
14.7

369
21.8

370
18.2

371
8.5

372
16.3

373
23.5

374
16.4

375
17.8

376
21.4

377
8.7

378
18.0

379
27.3

380
20.2

381
22.0

382
21.0

383
20.9

384
11.0

385
6.2

386
18.9

387
10.7

388
6.9

389
24.6

390
7.8

391
7.0

392
15.8

393
8.1

394
6.7

395
15.2

396
9.5

397
8.6

398
9.9

399
7.8

400
9.2

401
14.5

402
12.8

403
6.3

404
10.1

405
27.7

406
23.1

407
6.9

408
14.6

409
10.5

TABLE 41-7

Example No.
IC₅₀(μM)

410
8.4

411
12.8

412
19.0

413
11.3

414
4.6

415
18.5

416
5.8

417
2.2

418
10.9

419
24.8

420
18.6

421
19.5

423
20.0

424
29.0

425
28.1

426
26.1

427
17.4

428
23.0

429
7.7

430
4.6

431
6.2

432
6.3

433
18.6

434
19.5

435
17.1

436
14.0

437
19.5

438
21.9

439
18.9

440
22.6

441
21.4

442
6.3

443
8.9

444
7.4

445
9.2

446
11.1

447
15.8

Test Example 3: Inhibitory Effect on ³³PO₄Uptake into Human PiT-1-Expressing Cell

CHO cells were transfected with human PiT-1 expression plasmids or empty vectors to prepare human PiT-1-expressing cells and empty vector-expressing cells. The human PiT-1-expressing cells or the empty vector-expressing cells were inoculated to a 96-well plate and incubated overnight in a CO₂incubator. 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 KCl, 1 mM CaCl₂, 0.5 mM MgCl₂, 5 mM glucose, and 5 mM MES (pH 6.5)) supplemented with each compound at a final concentration of 0.24, 1.2, 6, or 30 μM or buffer B supplemented with DMSO. After a given time, a 1/20 volume of buffer A containing ³³PO₄was added thereto and reacted at room temperature. After washing with ice-cold buffer A, a liquid scintillator was added to each reaction mixture, and the amount of ³³PO₄uptake was measured using TopCount. The rate of inhibition was determined according to the following expression:

Rate (%) of inhibition=(1−(Amount of ³³PO₄uptake in the compound-supplemented well containing the human PiT-1-expressing cells−Amount of ³³PO₄uptake in the compound-supplemented well containing the empty vector-expressing cells)/(Amount of ³³PO₄uptake in the DMSO-supplemented well containing the human PiT-1-expressing cells −Amount of ³³PO₄uptake in the DMSO-supplemented well containing the empty vector-expressing cells))×100

TABLE 42

Example No.
IC₅₀(μM)

13
1.9

14
2.2

21
3.3

22
1.8

52
3.1

129
6.5

140
3.8

147
4.4

152
5.3

156
3.9

157
3.8

164
4.1

196
5.6

264
4.6

265
4.6

267
4.1

269
7.9

270
3.4

317
3.3

318
3.3

333
3.6

345
1.2

410
2.9

414
1.9

416
0.9

418
4.1

Test Example 4: Inhibitory Effect on ³³PO₄Uptake into Human PiT-2-Expressing Cell

CHO cells were transfected with human PiT-2 expression plasmids or empty vectors to prepare human PiT-2-expressing cells and empty vector-expressing cells. The human PiT-2-expressing cells or the empty vector-expressing cells were inoculated to a 96-well plate and incubated overnight in a CO₂incubator. 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 KCl, 1 mM CaCl₂, 0.5 mM MgCl₂, 5 mM glucose, and 5 mM MES (pH 6.5)) supplemented with each compound at a final concentration of 0.24, 1.2, 6, or 30 M or buffer B supplemented with DMSO. After a given time, a 1/20 volume of buffer A containing ³³PO₄was added thereto and reacted at room temperature. After washing with ice-cold buffer A, a liquid scintillator was added to each reaction mixture, and the amount of ³³PO₄uptake was measured using TopCount. The rate of inhibition was determined according to the following expression:

Rate (%) of inhibition=(1−(Amount of ³³PO₄uptake in the compound-supplemented well containing the human PiT-2-expressing cells−Amount of ³³PO₄uptake in the compound-supplemented well containing the empty vector-expressing cells)/(Amount of ³³PO₄uptake in the DMSO-supplemented well containing the human PiT-2-expressing cells −Amount of ³³PO₄uptake in the DMSO-supplemented well containing the empty vector-expressing cells))×100

TABLE 43

Example No.
IC₅₀(μM)

13
2.7

14
2.6

21
3.6

22
3.2

52
4.0

129
8.7

140
3.8

147
8.4

152
3.5

156
7.2

157
3.9

164
4.1

196
6.2

264
3.8

265
4.3

267
4.7

269
10.6

270
3.6

317
2.9

318
3.7

333
10.4

345
1.4

410
3.3

414
1.2

416
1.4

418
4.6

Test Example 5: Suppressive Effect on Rise in Serum Phosphorus Concentration of Adenine-Induced Renal Failure Rat

Adenine was forcedly administered orally to each Wistar male rat (7-8 weeks old) to impair renal functions and thereby prepare a hyperphosphatemia model (Katsumata K, Kusano K, Hirata M, Tsunemi K, Nagano N, Burke S K, Fukushima N. Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int. 2003 August; 64 (2): 441-50). Each test compound was mixed at a ratio of 0.1% of mass concentration with feed. The animal was fed with a given amount of the feed for 3 days. A group given feed non-supplemented with a test compound was used as a reference pathological group, and an adenine-unadministered group given feed non-supplemented with a test compound was used as a normal group. 3 days after the start of administration of the test compound, blood was collected from the jugular vein, and serum was collected. Serum phosphorus concentrations were measured by the Fiske-Subbarow method. The rate of suppression of a rise in serum phosphorus concentration was determined according to the following expression:

Rate (%) of suppression of a rise in serum phosphorus concentration=(1−[(Serum phosphorus concentration of the test compound-treated pathological group)−(Serum phosphorus concentration of the normal group)]/[(Serum phosphorus concentration of the reference pathological group)−(Serum phosphorus concentration of the normal group)])×100

As a result, each test compound was confirmed to have a suppressive effect on a rise in serum phosphorus concentration. Table 44 shows the rate (%) of suppression of a rise in serum phosphorus concentration by each test compound.

TABLE 44

Rate

of

Ex-

inhi-

am-

bi-

ple

tion

No.
Structural formula
Compound name
(%)

13

embedded image

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
25%

14

embedded image

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
39%

21

embedded image

(4aR)-1-[(2,3-Difluoro- 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
24%

22

embedded image

(4aR)-N-[2-(6-Cyano-5- methylpyrimidin-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
26%

52

embedded image

(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
20%

129

embedded image

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-ynoic acid
17%

140

embedded image

(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-(tri- fluoromethyl)pyridin-3-yl]phenyl]- 6,7-dihydro-5H-pyrrolo[1,2- b]pyridazine-3-carboxamide
39%

147

embedded image

(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]pyridazine-3-carboxamide
35%

152

embedded image

(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
26%

156

embedded image

(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]pyridazine-3- carboxamide
21%

157

embedded image

(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]pyridazine-3-carboxamide
30%

164

embedded image

(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]pyridazine-3- carboxamide; hydrochloride
14%

196

embedded image

(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
35%

264

embedded image

(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
15%

265

embedded image

(3S)-3-tert-Butyl-N-[4-chloro-2- [6-(trifluoromethyl)pyrimidin-4- yl]phenyl]-1-[[2,3-difluoro-4-(2- morpholin-4-ylethoxy) phenyl]methyl]- 4-hydroxy-2-methyl-6-oxo-3H- pyridazine-5-carboxamide
11%

267

embedded image

(3S)-3-tert-Butyl-N-[4-chloro-2- [6-(trifluoromethyl)pyridin- 3-yl]phenyl]-1-[[2,3-difluoro- 4-(2-morpholin-4-ylethoxy) phenyl]methyl]-4-hydroxy-2- methyl-6-oxo-3H-pyridazine-5- carboxamide
18%

269

embedded image

(3S)-3-tert-Butyl-N- [4-chloro-2-(6-methylsulfanyl- pyridin-3-yl)phenyl]-1-[[2,3- difluoro-4-(2-morpholin-4- ylethoxy)phenyl]methyl]-4- hydroxy-2-methyl-6-oxo- 3H-pyridazine-5- carboxamide
15%

270

embedded image

(3S)-3-tert-Butyl-N- [2-(6-cyano-5- methylpyrimidin-4-yl)-4- (trifluoromethyl)phenyl]-1-[[2,3- difluoro-4-(2-morpholin-4-yl- ethoxy)phenyl]methyl]-4-hydroxy- 2-methyl-6-oxo-3H-pyridazine-5- carboxamide
20%

317

embedded image

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
22%

318

embedded image

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
32%

333

embedded image

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
8%

345

embedded image

6-[[2,3-Difluoro-4-[2-[(2S)-2- (methoxymethyl)pyrrolidin-1- yl]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
19%

410

embedded image

7-[[2,3-Difluoro-4- [2-[methyl(oxetan-3-yl) 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
25%

Test Example 6: Suppressive Effect on Rise in Serum Phosphorus Concentration of Adenine-Induced Renal Failure Rat

Each adenine-induced renal failure rat was prepared in the same way as in Test Example 5. Each test compound was mixed at a ratio of 0.05% of mass concentration with feed. The animal was fed with a given amount of the feed for 8 days. A group given feed non-supplemented with a test compound was used as a reference pathological group, and an adenine-unadministered group given feed non-supplemented with a test compound was used as a normal group. 8 days after the start of administration of the test compound, blood was collected from the jugular vein, and serum was collected. Serum phosphorus concentrations were measured by the Fiske-Subbarow method. The rate of suppression of a rise in serum phosphorus concentration was determined according to the following expression:

Rate (%) of suppression of a rise in serum phosphorus concentration=(1−[(Serum phosphorus concentration of the test compound-treated pathological group)−(Serum phosphorus concentration of the normal group)]/[(Serum phosphorus concentration of the reference pathological group)−(Serum phosphorus concentration of the normal group)])×100

As a result, each test compound was confirmed to have a suppressive effect on a rise in serum phosphorus concentration. Table 45 shows the rate (%) of suppression of a rise in serum phosphorus concentration by each test compound.

TABLE 45

Rate

of

Ex-

inhi-

am-

bi-

ple

tion

No.
Structural formula
Compound name
(%)

414

embedded image

7-(4-(3-(Dimethylamino)-2,2- dimethylpropoxy)-2,3- difluorobenzyl)-10- hydroxy-6-methyl- 8-oxo-N-(4-(tri- fluoromethyl)-2-(6- (trifluoromethyl) pyrimidin-4- yl)phenyl)-6,7-diazaspiro [4.5]dec-9- ene-9-carboxamide
37%

416

embedded image

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
38%

418

embedded image

7-[[2,3-Difluoro-4- [4-[methyl- [(2S,3R,4R,5R)- 2,3,4,5,6-penta- hydroxyhexyl]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
38%

Test Example 7: Suppressive Effect on Rise in Serum Creatinine Concentration of Chronic Kidney Disease Model Rat

After removing one kidney from each Fischer male rat (6-7 weeks old), an anti-Thy 1.1 antibody was intravenously administered to the rat to prepare a chronic kidney disease model having persistently impaired renal function (Kusano K, Saito H, Segawa H, 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 April; 55 (2): 99-105.) A test compound was mixed with feed at a ratio of 0.1% or 0.3% of mass concentration and the mixture was fed to the animal for 14 weeks. A group given feed non-supplemented with the test compound was used as a reference pathological group, and a group neither subjected to the kidney removal nor antibody administration and given feed non-supplemented with the test compound was used as a normal group. Fourteen weeks after the start of administration of the test compound, blood was collected from the abdominal aorta and serum was collected. As an indicator of renal damage, serum creatinine concentrations were measured by an enzyme assay (creatinase-sarcosine oxidase-POD method). The rate of suppression of a rise in serum creatinine concentration was determined according to the following expression:

Rate (%) of suppression of a rise in serum creatinine concentration=(1−[(Serum creatinine concentration of the test compound-treated pathological group)−(Serum creatinine concentration of the normal group)]/[(Serum creatinine concentration of the reference pathological group)−(Serum creatinine concentration of the normal group)])×100

As a result, the test compound was confirmed to have a suppressive effect on a rise in serum creatinine concentration, namely, a suppressive effect on renal damage. Table 46 shows the rates (%) of suppression of a rise in serum creatinine concentration by the test compound.

TABLE 46

Rate of

Example

inhibition

No.
Structural formula
Compound name
dosage
(%)

14

embedded image

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
0.1% 0.3%
17% 24%

Test Example 8: Suppressive Effect on Rise in Serum Parathyroid Hormone Concentration of Chronic Kidney Disease Model Rat

Using serum collected from the same animal as that in test example 7 after 14 weeks from the start of administration of the test compound, concentrations of serum parathyroid hormone were measured by the ELISA method. The rate of suppression of a rise in concentration of serum parathyroid hormone was determined according to the following expression:

Rate (%) of suppression of a rise in concentration of serum parathyroid hormone=(1−[(Serum parathyroid hormone concentration of the test compound-treated pathological group)−(Serum parathyroid hormone concentration of the normal group)]/[(Serum parathyroid hormone concentration of the reference pathological group)−(Serum parathyroid hormone concentration of the normal group)])×100

As a result, the test compound was confirmed to have a suppressive effect on a rise in serum parathyroid hormone concentration, namely, a suppressive effect on secondary hyperparathyroidism. Table 47 shows the rates (%) of suppression of a rise in serum parathyroid hormone concentration by the test compound.

TABLE 47

Rate of

Example

inhibition

No.
Structural formula
Compound name
dosage
(%)

14

embedded image

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
0.1% 0.3%
13% 67%

Test Example 9: Suppressive Effect on Calcium Deposition in Blood Vessel of Chronic Kidney Disease Model Rat

From the same animal as that in Test Example 7, the thoracic aorta was collected 14 weeks after the start of administration of the test compound, and the dry weight was measured. The measured dry thoracic aorta was subjected to ashing and dissolved in a certain amount of hydrochloric acid, and then the calcium concentration in the solution was measured using OCPC method to determine the amount of calcium per gram of the thoracic aorta dry weight (Katsumata K, Kusano K, Hirata M, Tsunemi K, Nagano N, Burke S K, Fukushima N. Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int. 2003 August; 64(2): 441-450.) The rate of suppression of calcium deposition in blood vessel was determined according to the following expression:

Rate (%) of suppression of calcium deposition in blood vessel=(1−[(Amount of calcium per gram of dried blood vessel of the test compound-treated pathological group)−(Amount of calcium per gram of dried blood vessel of the normal group)]/[(Amount of calcium per gram of dried blood vessel of the reference pathological group)−(Amount of calcium per gram of dried blood vessel of the normal group)])×100

As a result, the test compound was confirmed to have a suppressive effect on calcium deposition in blood vessel, namely, a suppressive effect on vascular calcification. Table 48 shows the rates (%) of suppression of calcium deposition in blood vessel by the test compound.

TABLE 48

Rate of

Example

inhibition

No.
Structural formula
Compound name
dosage
(%)

14

embedded image

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
0.1% 0.3%
100% 100%

Test Example 10: Suppressive Effect on Rise in Serum Phosphorus Concentration by Combined Use with Sevelamer Carbonate

Adenine-induced renal failure rats were prepared in the same manner as in Test Example 5. Each of the animals was fed with a certain amount of one of the following feed for 14 days: feed containing a test compound at a concentration of 0.05% or 0.1% by mass; feed containing sevelamer carbonate at a concentration of 0.5% or 1.0% by mass; and feed containing the test compound at a concentration of 0.05% by mass in combination with sevelamer carbonate at a concentration of 0.5% by mass. A group given feed supplemented with neither the test compound nor sevelamer carbonate was used as a reference pathological group, and an adenine-unadministered group given feed supplemented with neither the test compound nor sevelamer carbonate was used as a normal group. Fourteen days after the start of administration of the test compound, blood was collected from the carotid artery and serum was collected. Serum phosphorus concentrations were measured by the Fiske-Subbarow method. The rate of suppression of a rise in serum phosphorus concentration was determined according to the following expression:

Rate (%) of suppression of a rise in serum phosphorus concentration=(1−[(Serum phosphorus concentration of the compound-treated pathological group)−(Serum phosphorus concentration of the normal group)]/[(Serum phosphorus concentration of the reference pathological group)−(Serum phosphorus concentration of the normal group)])×100

As a result, the combined use of the test compound and sevelamer carbonate was confirmed to have an additive suppressive effect on a rise in serum phosphorus concentration. Table 49 shows the rates (%) of suppression of a rise in serum phosphorus concentration by the test compound, sevelamer carbonate, and the combined use of the test compound and sevelamer carbonate.

TABLE 49

Suppression rate of

rise in serum phosphorus
test compound (compound of Example 14)

concentration (%)
0%
0.05%
0.1%

Sevelamer
0%
0%
61%
79%

carbonate
0.5%
49%
104%
—

1.0%
90%
—
—

Number	Date	Country	Kind
2013-051082	Mar 2013	JP	national
2013-132889	Jun 2013	JP	national
2014-187048	Sep 2014	JP	national

Number	Name	Date	Kind
20130029973	Hachiya et al.	Jan 2013	A1
20130053369	Hachiya et al.	Feb 2013	A1
20130336919	Lewis	Dec 2013	A1
20140329802	Hachiya et al.	Nov 2014	A1
20150031727	Miura et al.	Jan 2015	A1

Number	Date	Country
2010009183	Jan 2010	WO
2010022240	Feb 2010	WO
2011048611	Apr 2011	WO
2011136269	Nov 2011	WO
2012006474	Jan 2012	WO
2012006475	Jan 2012	WO
2012054367	Apr 2012	WO
2013062065	May 2013	WO

	Number	Date	Country
Parent	PCT/JP2014/056778	Mar 2014	US
Child	14852738		US

Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same

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