TW202237116A - A medicament for treating mycobacterial infection characterized by combining a cytochrome bc1 inhibitor with clarithromycin or azithromycin - Google Patents

Abstract

A medicament characterized in that (A) a compound represented by formula (I):

, or its pharmaceutically acceptable salt, wherein R ¹, R ², R ³and R ⁴are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; R ⁵is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or the like; R ⁶, R ⁷, R ⁸and R ⁹are each independently hydrogen atom, halogen or the like; X is CH or N; Y is CH or N; R ¹⁰is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; m is 0, 1, 2, 3 or 4; R ¹¹is halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; R ¹²is each independently halogen, hydroxy, cyano or the like; n is 0, 1, 2, 3 or 4; is combined with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and (C) clofazimine, or its pharmaceutically acceptable salt.

Description

Medicaments for the treatment of mycobacterial infections characterized by combinations of cytochrome bc1 inhibitors and clarithromycin or azithromycin

The present invention is concerned with novel combinations. The invention also relates to such combinations suitable as medicines, for example in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as nontuberculous mycobacteria. Specifically, the present invention relates to a medicine characterized in that a compound having cytochrome bc1 inhibitory activity or a pharmaceutically acceptable salt thereof and clarithromycin or azithromycin or a pharmaceutically acceptable salt thereof Acceptable salt, or a kind of medicine, it is characterized in that, the compound with cytochrome bc1 inhibitory activity or its pharmaceutically acceptable salt and clarithromycin or azithromycin and clofazimine (clofazimine) or its pharmaceutically acceptable of salt.

Mycobacteria has 95 well-characterized species. For centuries, two well-known mycobacterial species, namely Mycobacterium tuberculosis and M. leprae, have been known causes of great human suffering. Most other mycobacteria are present in the environment and their pathogenic potential has been recognized since the beginning of the last century. These mycobacteria are called nontuberculous mycobacteria (NTM). Although the incidence of tuberculosis (TB) is decreasing, NTM has caused new health problems worldwide. Lung disease caused by NTM is characterized by progressive irreversible lung damage and increased mortality. About 80% of lung NTM diseases are caused by Mycobacterium avium (MAC: M. avium , M. intracellulare , M. chimaera , Mycobacterium colombiense ( M. colombiense ), Mycobacterium arosiense ( M. arosiense ), Mycobacterium vulneris ( M. vulneris ), Mycobacterium bouchedurhonense ( M. timonense ), Mycobacterium marseillense , M. yongonense , M. paraintracellulare and M. lepraemurium ). The annual incidence of NTM lung disease varies from region to region with an overall alarming rate of increase ranging from 0.2/100,000 to 14.7/100,000. The disease is more prevalent after the age of 60, with estimated incidence in the United States from 19.6/100,000 in the period 1994-1996 to 26.7/100,000 in the period 2004-2006. Unlike TB, NTMs are opportunistic pathogens primarily found in immunocompromised patients or those with pre-existing lung conditions such as cystic fibrosis (CF), bronchiectasis, or chronic obstructive pulmonary disease (COPD) cause TB-like lung disease in In addition, postmenopausal women without pre-existing structural lung disease represent another risk group for NTM lung disease. These women (mainly older women of Caucasian or Asian descent) presented with nodular bronchiectasis as their NTM lung disease.

Currently, the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) recommend combination therapy for most patients with MAC lung disease. A thrice-weekly regimen of macrolide (clarithromycin or azithromycin), rifampin, and ethambutol is recommended for most patients with nodular/bronchiectasis disease. For patients with fibrocavitary MAC lung disease or severe nodular/bronchiectatic disease, daily doses of macrolides (clarithromycin or azithromycin), rifampicin or rifabutin, and ethambutol are recommended. Daily regimen with amikacin or streptomycin thrice weekly considered early in treatment. Patients should be treated until cultures are negative at 1 year of treatment. However, many patients are refractory to the aforementioned first-line therapies and cannot achieve sustained culture transformation. The limited success of current treatment regimens is caused in part by insufficient bactericidal activity and challenging compliance due to the frequent occurrence of adverse drug reactions. Therefore, there is a high medical need for new therapeutic agents (eg, combinations) that have the potential to show activity against drug-resistant mycobacteria, especially NTM.

此化合物稱為特拉西貝(Telacebec)且為用於治療結核病之新臨床候選物。 專利文獻10揭示貝達喹啉(bedaquiline)、特拉西貝及吡𠯤甲醯胺之組合。 專利文獻11揭示利福布汀、克拉黴素及氯法齊明之組合。 非專利文獻1揭示克拉黴素與氯法齊明之組合。 非專利文獻2揭示具有細胞色素bc1抑制活性之化合物與利福平之組合。 [專利文獻] Patent Documents 1 to 8 disclose various compounds having cytochrome bc1 inhibitory activity. Patent Document 9 discloses various compounds having cytochrome bc1 inhibitory activity. For example, the following compounds are disclosed.

This compound is called Telacebec and is a new clinical candidate for the treatment of tuberculosis. Patent Document 10 discloses a combination of bedaquiline, telacibe, and pyridoxamide. Patent Document 11 discloses a combination of rifabutin, clarithromycin and clofazimine. Non-Patent Document 1 discloses a combination of clarithromycin and clofazimine. Non-Patent Document 2 discloses a combination of a compound having cytochrome bc1 inhibitory activity and rifampicin. [Patent Document]

Patent Document 1: WO2011/057145 Patent Document 2: WO2014/015167 Patent Document 3: WO2017/049321 Patent Document 4: US2017/0313697 Patent Document 5: WO2017/001660 Patent Document 6: WO2017/001661 Patent Document 7: WO2017/216281 Patent Document 8: WO2017/216283 Patent Document 9: WO2011/113606 Patent Document 10: WO2018/158280 Patent Document 11: US2016/0228464 [Non-patent literature]

Non-Patent Document 1: Antimicrobial Agents and Chemotherapy, February 2016, Volume 60, Issue 2, 1097-1105 Non-Patent Literature 2: Antimicrobial Agents and Chemotherapy, August 2016, Volume 60, Issue 8, 5018-5022

[Problems to be solved in the present invention]

One object of the present invention is to provide a medicament suitable for treating or preventing mycobacterial infection with few side effects. [means to solve the problem]

As a result of extensive research in order to solve the above problems, the present inventors have recently found that a novel combination of a cytochrome bc1 inhibitor and clarithromycin or azithromycin or a pharmaceutically acceptable salt thereof, or Novel combinations of cytochrome bc1 inhibitors, clarithromycin or azithromycin and clofazimine or pharmaceutically acceptable salts thereof are particularly effective in the prevention and/or treatment of mycobacterial infections, especially nontuberculous mycobacterial infections .

Clarithromycin is one of the macrolides recommended by the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) as a combination regimen for first-line therapy of MAC disease. Clarithromycin and azithromycin are the only (single) agents used to treat MAC disease, and there is a correlation between their in vitro sensitivity and in vivo (clinical) response. Specifically, treatment success was associated with macrolide sensitivity in vitro, while conversely patients with macrolide-resistant MAC isolates did not respond favorably to macrolide-containing regimens. This fundamental relationship has not been established for any other agent treating MAC lung disease.

Clofazimine, an orally administered drug approved for the treatment of leprosy, is currently repurposed as an anti-TB drug. A retrospective review reported that despite relapses, a significantly greater proportion of patients with MAC-infected lung disease treated with clofazimine converted to negative cultures. In vitro, its MIC ranged from 1 to 4 μg/mL against M. avium and was <1 μg/mL against most M. intracellulare isolates.

Azithromycin is one of the macrolides recommended by ATS/IDSA as a combination regimen for first-line therapy of MAC disease. Since clarithromycin inhibits cytochrome P-450 (CYP) 3A and affects the metabolism of other drugs, but azithromycin does not inhibit CYP3A, azithromycin is preferentially used in the treatment of MAC diseases.

Recently, with the emergence of bedaquiline for the treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been identified as an important target and vulnerable component of mycobacterial metabolism. Taking advantage of TB's dependence on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. The cytochrome bcl complex is one of the validated targets for antimycobacterial drug development. The complex is assembled with three subunits qcrA, qcrB and qcrC. Tracibe, one of the qcrB inhibitors, inhibited the growth of TB not only in vitro but also in an in vivo mouse model.

。 由式(I)表示之化合物或其醫藥學上可接受之鹽具有優良的細胞色素bc1抑制活性。 舉例而言，WO2021/050708中描述屬於式(I)之以下化合物具有優良的細胞色素bc1抑制活性：

。 [本發明之若干實施例的簡要描述] The cytochrome bc1 inhibitor of the present invention can be the compound of following general formula (I):

. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof has excellent cytochrome bc1 inhibitory activity. For example, the following compounds belonging to formula (I) described in WO2021/050708 have excellent cytochrome bcl inhibitory activity:

. [Brief Description of Several Embodiments of the Invention]

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； 組合使用 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (2)如上述(1)之藥物，其中R ¹及R ⁴為氫原子。 (3)如上述(1)或(2)之藥物，其中R ²為氫原子、鹵素或經取代或未經取代之烷基。 (4)如上述(1)至(3)中任一項之藥物，其中R ³為氫原子或鹵素。 (5)如上述(1)至(4)中任一項之藥物，其中R ⁵為經取代或未經取代之烷基。 (6)如上述(1)至(5)中任一項之藥物，其中R ⁶、R ⁸及R ⁹為氫原子，且R ⁷為鹵素。 (7)如上述(1)至(6)中任一項之藥物，其中X為N。 (8)如上述(1)至(7)中任一項之藥物，其中Y為N。 (9)如上述(1)至(8)中任一項之藥物，其中m為1。 (10)如上述(9)之藥物，其中R ¹⁰為經取代或未經取代之烷基。 (11)如上述(1)至(10)中任一項之藥物，其中R ¹¹為經取代或未經取代之烷氧基。 (12)如上述(1)至(11)中任一項之藥物，其中n為0。 (13)如上述(1)之藥物，其中(A)為選自由以下組成之群的化合物：

或其醫藥學上可接受之鹽。 (14)如上述(1)至(13)中任一項之藥物，其中(B)為克拉黴素或其醫藥學上可接受之鹽。 (15)如上述(1)至(14)中任一項之藥物，其中(A)及(B)係同時、依序或間隔投與。 (16)如上述(1)至(14)中任一項之藥物，其中該藥物為組合藥物。 (17)如上述(1)至(16)中任一項之藥物，其中該藥物係用於治療或預防分枝桿菌感染。 (18)一種增強(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽與如上述(1)之由式(I)表示之化合物或其醫藥學上可接受之鹽。 (19)一種增強如上述(1)之由式(I)表示之化合物或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與如上述(1)之由式(I)表示之化合物或其醫藥學上可接受之鹽與(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽。 (20)如上述(18)之方法，其中該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽係與治療有效量的如上述(1)之由式(I)表示之化合物或其醫藥學上可接受之鹽同時、依序或間隔投與。 (21)如上述(19)之方法，其中如上述(1)之由式(I)表示之化合物或其醫藥學上可接受之鹽係與治療有效量的(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽同時、依序或間隔投與。 (22)一種治療分枝桿菌感染之方法，其包含向需要治療分枝桿菌感染之個體投與治療有效量的以下之組合： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4；及 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (23)如上述(22)之方法，其中(A)由式(I)表示之化合物或其醫藥學上可接受之鹽及(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽係同時、依序或間隔投與。 (24)一種醫藥組合物或套組，其包含： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4；及 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (25)一種藥物，其特徵在於，(A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； 組合使用 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 (26)如上述(25)之藥物，其中R ¹及R ⁴為氫原子。 (27)如上述(25)或(26)之藥物，其中R ²為氫原子、鹵素或經取代或未經取代之烷基。 (28)如上述(25)至(27)中任一項之藥物，其中R ³為氫原子或鹵素。 (29)如上述(25)至(28)中任一項之藥物，其中R ⁵為經取代或未經取代之烷基。 (30)如上述(25)至(29)中任一項之藥物，其中R ⁶、R ⁸及R ⁹為氫原子，且R ⁷為鹵素。 (31)如上述(25)至(30)中任一項之藥物，其中X為N。 (32)如上述(25)至(31)中任一項之藥物，其中Y為N。 (33)如上述(25)至(32)中任一項之藥物，其中m為1。 (34)如上述(33)之藥物，其中R ¹⁰為經取代或未經取代之烷基。 (35)如上述(25)至(34)中任一項之藥物，其中R ¹¹為經取代或未經取代之烷氧基。 (36)如上述(25)至(35)中任一項之藥物，其中n為0。 (37)如上述(25)之藥物，其中(A)為選自由以下組成之群的化合物：

或其醫藥學上可接受之鹽。 (38)如上述(25)至(37)中任一項之藥物，其中(B)為克拉黴素或其醫藥學上可接受之鹽。 (39)如上述(25)至(38)中任一項之藥物，其中(A)、(B)及(C)係同時、依序或間隔投與。 (40)如上述(25)至(38)中任一項之藥物，其中該藥物為組合藥物。 (41)如上述(25)至(40)中任一項之藥物，其中該藥物係用於治療或預防分枝桿菌感染。 (42)一種增強(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽與如上述(25)之由式(I)表示之化合物或其醫藥學上可接受之鹽。 (43)一種增強如上述(25)之由式(I)表示之化合物或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與如上述(25)之由式(I)表示之化合物或其醫藥學上可接受之鹽，與(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽。 (44)如上述(42)之方法，其中該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽係與治療有效量的如上述(25)之由式(I)表示之化合物或其醫藥學上可接受之鹽同時、依序或間隔投與。 (45)如上述(43)之方法，其中如上述(25)之由式(I)表示之化合物或其醫藥學上可接受之鹽係與治療有效量的(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽同時、依序或間隔投與。 (46)一種治療分枝桿菌感染之方法，其包含向需要治療分枝桿菌感染之個體投與治療有效量的以下之組合： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 (47)如上述(46)之方法，其中(A)由式(I)表示之化合物或其醫藥學上可接受之鹽、(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽係同時、依序或間隔投與。 (48)一種醫藥組合物或套組，其包含： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 (49)一種藥物，其特徵在於，(A)下文定義之化合物

或其醫藥學上可接受之鹽； 組合使用 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (50)如上述(49)之藥物，其中(B)為克拉黴素或其醫藥學上可接受之鹽。 (51)如上述(49)或(50)之藥物，其中(A)及(B)同係時、依序或間隔投與。 (52)如上述(49)或(50)之藥物，其中該藥物為組合藥物。 (53)如上述(49)至(52)中任一項之藥物，其中該藥物係用於治療或預防分枝桿菌感染。 (54)一種增強(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽與如上述(49)之化合物(A)或其醫藥學上可接受之鹽。 (55)一種增強如上述(49)之化合物(A)或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與如上述(49)之化合物(A)或其醫藥學上可接受之鹽與(B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (56)如上述(54)之方法，其中該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽係與治療有效量的如上述(49)之化合物(A)或其醫藥學上可接受之鹽同時、依序或間隔投與。 (57)如上述(55)之方法，其中如上述(49)之化合物(A)或其醫藥學上可接受之鹽係與治療有效量的(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽同時、依序或間隔投與。 (58)一種治療分枝桿菌感染之方法，其包含向需要治療分枝桿菌感染之個體投與治療有效量的以下之組合： (A)下文定義之化合物

或其醫藥學上可接受之鹽；及 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (59)如上述(58)之方法，其中該化合物(A)或其醫藥學上可接受之鹽及(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽係同時、依序或間隔投與。 (60)一種醫藥組合物或套組，其包含： (A)下文定義之化合物

或其醫藥學上可接受之鹽；及 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 (1')一種藥物，其特徵在於，(A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； 組合使用 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 (2')如上述(1')之藥物，其中R ¹及R ⁴為氫原子。 (3')如上述(1')之藥物，其中R ²為氫原子、鹵素或經取代或未經取代之烷基。 (4')如上述(1')之藥物，其中R ³為氫原子或鹵素。 (5')如上述(1')之藥物，其中R ⁵為經取代或未經取代之烷基。 (6')如上述(1')之藥物，其中R ⁶、R ⁸及R ⁹為氫原子，且R ⁷為鹵素。 (7')如上述(1')之藥物，其中X為N。 (8')如上述(1')之藥物，其中Y為N。 (9')如上述(1')之藥物，其中m為1。 (10')如上述(9')之藥物，其中R ¹⁰為經取代或未經取代之烷基。 (11')如上述(1')之藥物，其中R ¹¹為經取代或未經取代之烷氧基。 (12')如上述(1')之藥物，其中n為0。 (13')如上述(1')之藥物，其中(A)為選自由以下組成之群的化合物：

或其醫藥學上可接受之鹽。 (14')如上述(1')之藥物，其中(B)為克拉黴素或其醫藥學上可接受之鹽。 (15')如上述(1')之藥物，其中(A)、(B)及(C)係同時、依序或間隔投與。 (16')如上述(1')之藥物，其中該藥物為組合藥物。 (17')如上述(1')之藥物，其中該藥物係用於治療或預防分枝桿菌感染。 (18')一種增強(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽與如上述(1')之由式(I)表示之化合物或其醫藥學上可接受之鹽。 (19')一種增強如上述(1')之由式(I)表示之化合物或其醫藥學上可接受之鹽的抗細菌活性之方法，其包含投與如上述(1')之由式(I)表示之化合物或其醫藥學上可接受之鹽與(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽。 (20')如上述(18')之方法，其中該(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽係與治療有效量的如上述(1')之由式(I)表示之化合物或其醫藥學上可接受之鹽同時、依序或間隔投與。 (21')如上述(19')之方法，其中如上述(1')之由式(I)表示之化合物或其醫藥學上可接受之鹽係與治療有效量的(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及/或(C)氯法齊明或其醫藥學上可接受之鹽同時、依序或間隔投與。 (22')一種治療分枝桿菌感染之方法，其包含向需要治療分枝桿菌感染之個體投與治療有效量的以下之組合： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 (23')如上述(22')之方法，其中(A)由式(I)表示之化合物或其醫藥學上可接受之鹽、(B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽係同時、依序或間隔投與。 (24')一種醫藥組合物或套組，其包含： (A)由式(I)表示之化合物：

或其醫藥學上可接受之鹽， 其中 R ¹、R ²、R ³及R ⁴各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； R ⁵為氫原子、鹵素、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； R ⁶、R ⁷、R ⁸及R ⁹各自獨立地為氫原子、鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基，其限制條件為R ⁶、R ⁷、R ⁸及R ⁹不同時為氫原子； X為CH或N； Y為CH或N； R ¹⁰各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基或經取代或未經取代之炔基； m為0、1、2、3或4； R ¹¹為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基、經取代或未經取代之炔氧基、或五氟硫基； R ¹²各自獨立地為鹵素、羥基、氰基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之烷氧基、經取代或未經取代之烯氧基或經取代或未經取代之炔氧基； n為0、1、2、3或4； (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽；及 (C)氯法齊明或其醫藥學上可接受之鹽。 [本發明之效果] (1) A drug characterized in that (A) is a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof is used in combination. (2) The drug according to (1) above, wherein R ¹ and R ⁴ are hydrogen atoms. (3) The drug according to (1) or (2) above, wherein R ² is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group. (4) The drug according to any one of (1) to (3) above, wherein R ³ is a hydrogen atom or a halogen. (5) The drug according to any one of (1) to (4) above, wherein R ⁵ is a substituted or unsubstituted alkyl group. (6) The drug according to any one of (1) to (5) above, wherein R ⁶ , R ⁸ and R ⁹ are hydrogen atoms, and R ⁷ is halogen. (7) The drug according to any one of (1) to (6) above, wherein X is N. (8) The drug according to any one of (1) to (7) above, wherein Y is N. (9) The drug according to any one of (1) to (8) above, wherein m is 1. (10) The drug according to (9) above, wherein R ¹⁰ is a substituted or unsubstituted alkyl group. (11) The drug according to any one of (1) to (10) above, wherein R ¹¹ is a substituted or unsubstituted alkoxy group. (12) The drug according to any one of (1) to (11) above, wherein n is 0. (13) The drug according to (1) above, wherein (A) is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. (14) The drug according to any one of (1) to (13) above, wherein (B) is clarithromycin or a pharmaceutically acceptable salt thereof. (15) The drug according to any one of (1) to (14) above, wherein (A) and (B) are administered simultaneously, sequentially or at intervals. (16) The drug according to any one of (1) to (14) above, wherein the drug is a combination drug. (17) The drug according to any one of (1) to (16) above, wherein the drug is used for treating or preventing mycobacterial infection. (18) A method for enhancing the antibacterial activity of (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof, comprising administering the (B) clarithromycin or A pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and a compound represented by formula (I) as in the above (1) or a pharmaceutically acceptable salt thereof. (19) A method for enhancing the antibacterial activity of the compound represented by formula (I) as in the above (1) or a pharmaceutically acceptable salt thereof, comprising administering the compound represented by the formula (I) as in the above (1). The indicated compound or its pharmaceutically acceptable salt and (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt. (20) The method of (18) above, wherein (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof is combined with a therapeutically effective amount of the above (1) The compounds represented by formula (I) or pharmaceutically acceptable salts thereof are administered simultaneously, sequentially or at intervals. (21) The method of (19) above, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as in (1) above is combined with a therapeutically effective amount of (B) clarithromycin or its medicinal product A pharmaceutically acceptable salt or azithromycin or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or at intervals. (22) A method of treating mycobacterial infection, comprising administering a therapeutically effective amount of a combination of the following to an individual in need of treatment of mycobacterial infection: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (23) The method according to (22) above, wherein (A) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin Or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or at intervals. (24) A pharmaceutical composition or kit comprising: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (25) A drug characterized in that (A) is a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof are used in combination. (26) The drug according to (25) above, wherein R ¹ and R ⁴ are hydrogen atoms. (27) The drug according to (25) or (26) above, wherein R ² is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. (28) The drug according to any one of (25) to (27) above, wherein R ³ is a hydrogen atom or a halogen. (29) The drug according to any one of (25) to (28) above, wherein R ⁵ is a substituted or unsubstituted alkyl group. (30) The drug according to any one of (25) to (29) above, wherein R ⁶ , R ⁸ and R ⁹ are hydrogen atoms, and R ⁷ is halogen. (31) The drug according to any one of (25) to (30) above, wherein X is N. (32) The drug according to any one of (25) to (31) above, wherein Y is N. (33) The drug according to any one of (25) to (32) above, wherein m is 1. (34) The drug according to (33) above, wherein R ¹⁰ is a substituted or unsubstituted alkyl group. (35) The drug according to any one of (25) to (34) above, wherein R ¹¹ is a substituted or unsubstituted alkoxy group. (36) The drug according to any one of (25) to (35) above, wherein n is 0. (37) The drug according to (25) above, wherein (A) is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. (38) The drug according to any one of (25) to (37) above, wherein (B) is clarithromycin or a pharmaceutically acceptable salt thereof. (39) The drug according to any one of (25) to (38) above, wherein (A), (B) and (C) are administered simultaneously, sequentially or at intervals. (40) The drug according to any one of (25) to (38) above, wherein the drug is a combination drug. (41) The medicament according to any one of (25) to (40) above, wherein the medicament is used for treating or preventing mycobacterial infection. (42) An enhanced (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or a pharmaceutically acceptable salt thereof The antibacterial activity method of the present invention, it comprises administering said (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine or its pharmaceutically The compound represented by the formula (I) as above (25) or a pharmaceutically acceptable salt thereof. (43) A method for enhancing the antibacterial activity of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described in (25) above, which comprises administering the compound represented by formula (I) as described in (25) above. The indicated compound or its pharmaceutically acceptable salt, and (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine or its Pharmaceutically acceptable salts. (44) The method of (42) above, wherein the (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or A pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described in (25) above. (45) The method as in the above (43), wherein the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as in the above (25) is combined with a therapeutically effective amount of (B) clarithromycin or its medicine Simultaneous, sequential or interval administration of a pharmaceutically acceptable salt or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or a pharmaceutically acceptable salt thereof. (46) A method of treating mycobacterial infection, comprising administering to an individual in need of treatment of mycobacterial infection a therapeutically effective amount of a combination of: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof. (47) The method according to (46) above, wherein (A) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin Or a pharmaceutically acceptable salt thereof and (C) clofazimine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or at intervals. (48) A pharmaceutical composition or kit comprising: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof. (49) A drug characterized in that (A) a compound defined below

or a pharmaceutically acceptable salt thereof; combined use of (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (50) The drug according to (49) above, wherein (B) is clarithromycin or a pharmaceutically acceptable salt thereof. (51) The drug of (49) or (50) above, wherein (A) and (B) are administered simultaneously, sequentially or at intervals. (52) The drug as described in (49) or (50) above, wherein the drug is a combination drug. (53) The medicament according to any one of (49) to (52) above, wherein the medicament is used for treating or preventing mycobacterial infection. (54) A method for enhancing the antibacterial activity of (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof, comprising administering the (B) clarithromycin or A pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and the compound (A) as described in (49) above or a pharmaceutically acceptable salt thereof. (55) A method for enhancing the antibacterial activity of the compound (A) as in the above (49) or a pharmaceutically acceptable salt thereof, comprising administering the compound (A) as in the above (49) or a pharmaceutically acceptable salt thereof Acceptable salts and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (56) The method of (54) above, wherein (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof is combined with a therapeutically effective amount of the above-mentioned (49) Compound (A) or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or at intervals. (57) The method as in the above (55), wherein the compound (A) or a pharmaceutically acceptable salt thereof as in the above (49) is combined with a therapeutically effective amount of (B) clarithromycin or a pharmaceutically acceptable or azithromycin or a pharmaceutically acceptable salt thereof were administered simultaneously, sequentially or at intervals. (58) A method of treating a mycobacterial infection comprising administering to an individual in need of treatment of a mycobacterial infection a therapeutically effective amount of a combination of: (A) a compound as defined below

or a pharmaceutically acceptable salt thereof; and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (59) The method of (58) above, wherein the compound (A) or a pharmaceutically acceptable salt thereof and (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof The salts received are administered simultaneously, sequentially or at intervals. (60) A pharmaceutical composition or kit comprising: (A) a compound as defined below

or a pharmaceutically acceptable salt thereof; and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. (1') A drug characterized in that (A) is a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof are used in combination. (2') The drug according to (1') above, wherein R ¹ and R ⁴ are hydrogen atoms. (3') The drug according to (1') above, wherein R ² is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. (4') The drug according to (1') above, wherein R ³ is a hydrogen atom or a halogen. (5') The drug of (1') above, wherein R ⁵ is a substituted or unsubstituted alkyl group. (6') The drug according to (1') above, wherein R ⁶ , R ⁸ and R ⁹ are hydrogen atoms, and R ⁷ is halogen. (7') The drug according to (1') above, wherein X is N. (8') The drug according to (1') above, wherein Y is N. (9') The drug according to (1') above, wherein m is 1. (10') The drug of (9') above, wherein R ¹⁰ is a substituted or unsubstituted alkyl group. (11') The drug according to (1') above, wherein R ¹¹ is a substituted or unsubstituted alkoxy group. (12') The drug according to (1') above, wherein n is 0. (13') The drug according to (1') above, wherein (A) is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. (14') The drug according to (1') above, wherein (B) is clarithromycin or a pharmaceutically acceptable salt thereof. (15') The drug of (1') above, wherein (A), (B) and (C) are administered simultaneously, sequentially or at intervals. (16') The drug according to (1') above, wherein the drug is a combination drug. (17') The drug according to (1') above, wherein the drug is used for treating or preventing mycobacterial infection. (18') An enhanced (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or a pharmaceutically acceptable salt thereof A method for antibacterial activity of a salt comprising administering (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and (C) clofazimine or a pharmaceutically acceptable salt thereof A pharmaceutically acceptable salt and a compound represented by formula (I) as in (1') above or a pharmaceutically acceptable salt thereof. (19') A method for enhancing the antibacterial activity of the compound represented by formula (I) as in (1') above or a pharmaceutically acceptable salt thereof, comprising administering the compound represented by formula (1') as above (I) Compound or its pharmaceutically acceptable salt and (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine or a pharmaceutically acceptable salt thereof. (20') The method of (18') above, wherein the (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazil The compound or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described in (1') above. (21') The method of (19') above, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as in (1') above is combined with a therapeutically effective amount of (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or at intervals. (22') A method of treating mycobacterial infection, comprising administering to an individual in need of treatment of mycobacterial infection a therapeutically effective amount of a combination of: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof. (23') The method of (22') above, wherein (A) the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (B) clarithromycin or a pharmaceutically acceptable salt thereof Or azithromycin or a pharmaceutically acceptable salt thereof and (C) clofazimine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or at intervals. (24') A pharmaceutical composition or kit comprising: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof. [Effects of the present invention]

The medicine of the present invention is suitable for treating mycobacterium infection, especially non-tuberculous mycobacterium infection.

Each term used in this specification will be described below. In this specification, even when each term is used alone or in combination with other terms, the term has the same meaning. The term "consisting of" means having only the recited components or elements. The term "comprising" means not being limited to components and not excluding unrecited elements. When used in conjunction with the term "comprising" in the claims and/or this specification, the use of the word "a (a/an)" may mean "one", but it is also used in conjunction with "one or more "/kind", "at least one/kind" and "one/kind or more than one/kind" have the same meaning.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof in (A) is described above and below.

The term "halogen" includes fluorine atom, chlorine atom, bromine atom and iodine atom. Fluorine atom and chlorine atom are particularly preferable.

The term "alkyl" includes C1 to C15, preferably C1 to C10, more preferably C1 to C6 and more preferably C1 to C4 straight or branched chain hydrocarbon groups. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl n-heptyl, iso-heptyl, n-octyl, isooctyl, n-nonyl and n-decyl. A preferred example of "alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl or n-pentyl. More preferred examples are methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

The term "alkenyl" includes C2 to C15, preferably C2 to C10, more preferably C2 to C6 and more preferably C2 to C4 straight or branched chain hydrocarbon groups having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexyl Alkenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl Alkenyl. A preferred example of "alkenyl" is vinyl, allyl, propenyl, isopropenyl or butenyl.

The term "alkynyl" includes C2 to C8 straight or branched alkynyl groups having one or more triple bonds in the above "alkyl", and examples thereof include ethynyl, propynyl, butynyl and the like group. In addition, "alkynyl" may have a double bond.

The term "alkoxy" means a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy. A preferred example of "alkoxy" is methoxy, ethoxy, n-propoxy, isopropoxy or tertiary butoxy.

The term "alkenyloxy" means a group in which the above "alkenyl" is bonded to an oxygen atom. Examples include ethyleneoxy, allyloxy, 1-n-propenyloxy, 2-n-butenyloxy, 2-n-pentenyloxy, 2-n-hexenyloxy, 2-n-heptenyloxy and 2 - n-octenyloxy.

The term "alkynyloxy" means a group in which the above-mentioned "alkynyl" is bonded to an oxygen atom. Examples include ethynyloxy, 1-n-propynyloxy, 2-n-propynyloxy, 2-n-butynyloxy, 2-n-pentynyloxy, 2-n-hexynyloxy, 2-n-heptynyloxy Alkynyloxy and 2-n-octynyloxy.

"Substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkoxy", "substituted alkenyloxy" and "substituted alkynyloxy" The substituents of include the following substituents. A carbon atom at any position may be bonded to one or more groups selected from the following substituents. Substituents: halogen, hydroxyl, carboxyl, amine, imino, hydroxylamine, hydroxylimino, formyl, formyloxy, carbamoyl, sulfamoyl, mercapto, sulfinic acid Group, sulfonic acid group, thioformyl group, thiocarboxy group, dithiocarboxy group, aminothioformyl group, cyano group, nitro group, nitroso group, azido group, hydrazine group, urea group, formamidine group, guanidine group , trialkylsilyl, alkoxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamine, alkenylamino, alkynylamine Alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamine, alkenylcarbonylamine, alkynylcarbonylamine, alkylsulfonamide, alkenylsulfonamide group, alkynylsulfonamido group, alkylimino group, alkenylimino group, alkynylimino group, alkylcarbonylimino group, alkenylcarbonylimino group, alkynylcarbonylimino group, alkoxy Alkylimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxy Carbonyl, Alkylthiol, Alkenylthiol, Alkynylthiol, Alkylsulfinyl, Alkenylsulfinyl, Alkynylsulfinyl, Alkylaminoformyl, Alkenyl Aminoformyl, alkynylaminoformyl, alkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, aromatic carbocyclic, non-aromatic carbocyclic, aromatic heterocycle Base, non-aromatic heterocyclyl, aromatic carbocyclyloxy, non-aromatic carbocyclyloxy, aromatic heterocyclyloxy, non-aromatic heterocyclyloxy, aromatic carbocyclylcarbonyl, Non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-aromatic heterocyclylcarbonyl, aromatic carbocyclyloxycarbonyl, non-aromatic carbocyclyloxycarbonyl, aromatic heterocyclyloxycarbonyl , non-aromatic heterocyclyloxycarbonyl, aromatic carbocyclylalkoxy, non-aromatic carbocyclylalkoxy, aromatic heterocyclylalkoxy, non-aromatic heterocyclylalkoxy, aromatic Aromatic carbocyclylalkoxycarbonyl, non-aromatic carbocyclylalkoxycarbonyl, aromatic heterocyclylalkoxycarbonyl, non-aromatic heterocyclylalkoxycarbonyl, aromatic carbocyclylalkylamine , non-aromatic carbocyclylalkylamine, aromatic heterocycloalkylamine, non-aromatic heterocycloalkylamine, aromatic carbocyclyl mercapto, non-aromatic carbocyclyl mercapto, Aromatic heterocyclyl mercapto, non-aromatic heterocyclyl mercapto, non-aromatic carbocyclyl sulfonyl, aromatic carbocyclyl sulfonyl, aromatic heterocyclyl sulfonyl and non-aromatic Heterocyclylsulfonyl. Preferred substituents: halogen, hydroxyl, carboxyl, amino, imino, hydroxylamine, hydroxylimino, formyl, formyloxy, carbamoyl, sulfamoyl, mercapto, Sulfinic acid group, sulfonic acid group, thioformyl group, thiocarboxy group, dithiocarboxy group, aminothioformyl group, cyano group, nitro group, nitroso group, azido group, hydrazine group, urea group, formamidine group , guanidino, trialkylsilyl, alkoxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, Alkynylamino, Alkylsulfonyl, Alkenylsulfonyl, Alkynylsulfonyl, Alkylcarbonylamino, Alkenylcarbonylamine, Alkynylcarbonylamino, Alkylsulfonylamide, Alkenyl Sulfonamide, alkynylsulfonamide, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimine, alkenylcarbonylimine, alkynylcarbonylimine , alkoxyimino, alkenyloxyimino, alkynoxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkenyloxycarbonyl, Alkynyloxycarbonyl, alkylsulfenyl, alkenylsulfenyl, alkynylsulfenyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylaminoformyl , alkenylaminoformyl, alkynylaminoformyl, alkylaminosulfonyl, alkenylaminosulfonyl and alkynylaminosulfonyl. More preferable substituents: halogen, hydroxyl, amino, cyano, alkoxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylamino, alkenylamino and alkynylamino. Particularly preferred substituents: halogen, hydroxy, amine, cyano, alkoxy and alkylamine.

The term "haloalkyl" includes groups in which one or more hydrogen atoms bonded to the carbon atoms of the above-mentioned "alkyl" are replaced with the above-mentioned "halogen". Examples include monofluoromethyl, monofluoroethyl, monofluoro-n-propyl, 2,2,3,3,3-n-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2 ,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl and 1,1,1-trifluoro-n-propan-2-yl. A preferred example of "haloalkyl" is trifluoromethyl and trichloromethyl.

The term "haloalkyloxy" means a group in which the above-mentioned "haloalkyl" is bonded to an oxygen atom. Examples include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy and trichloroethoxy. A preferred example of "haloalkyloxy" is trifluoromethoxy and trichloromethoxy.

The term "alkylcarbonyl" means a group in which the above-mentioned "alkyl" is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, tertiary butylcarbonyl, isobutylcarbonyl, secondary butylcarbonyl, n-pentylcarbonyl, isopentyl carbonyl and n-hexylcarbonyl. A preferred example of "alkylcarbonyl" is methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.

The term "alkenylcarbonyl" means a group in which the above-mentioned "alkenyl" is bonded to a carbonyl group. Examples include vinylcarbonyl, allylcarbonyl and n-propenylcarbonyl.

The term "alkynylcarbonyl" means a group in which the above-mentioned "alkynyl" is bonded to a carbonyl group. Examples include ethynylcarbonyl and n-propynylcarbonyl.

The term "alkylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "alkyl group". Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, and N-methyl-N-ethyl Amino. A preferred example of "alkylamino group" is methylamino group and ethylamino group.

The term "alkenylamino group" means a group in which a hydrogen atom attached to a nitrogen atom of an amine group is replaced by the above-mentioned "alkenyl group". For example, it includes vinylamine groups, propenylamine groups and the like. Another hydrogen atom connected to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkynylamino group" means a group in which a hydrogen atom attached to a nitrogen atom of an amine group is replaced by the above-mentioned "alkynyl group". It includes, for example, ethynylamine groups, propynylamine groups, and the like. Another hydrogen atom connected to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkylsulfonyl" means a group in which the above-mentioned "alkyl" is bonded to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tertiary butylsulfonyl, isobutylsulfonyl and Secondary butylsulfonyl. A preferred example of "alkylsulfonyl" is methylsulfonyl and ethylsulfonyl.

The term "alkenylsulfonyl" means a group in which the above-mentioned "alkenyl" is bonded to a sulfonyl group. Examples include vinylsulfonyl, allylsulfonyl and n-propenylsulfonyl.

The term "alkynylsulfonyl" means a group in which the above-mentioned "alkynyl" is bonded to a sulfonyl group. Examples include ethynylsulfonyl and n-propynylsulfonyl.

The term "alkylcarbonylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "alkylcarbonyl group". Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropyl Carbonylamine, n-butylcarbonylamine, tertiary butylcarbonylamine, isobutylcarbonylamine and secondary butylcarbonylamine. Another hydrogen atom bonded to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkenylcarbonylamino group" means a group in which a hydrogen atom bonded to a nitrogen atom of an amine group is replaced by the above-mentioned "alkenylcarbonyl group". For example, it includes vinylcarbonylamine, propenylcarbonylamine and the like. Another hydrogen atom bonded to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkynylcarbonylamino group" means a group in which a hydrogen atom bonded to a nitrogen atom of an amine group is replaced by the above-mentioned "alkynylcarbonyl group". For example, it includes ethynylcarbonylamine, propynylcarbonylamine and the like. Another hydrogen atom bonded to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkylsulfonylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "alkylsulfonyl group". Examples include methylsulfonylamide, dimethylsulfonylamide, ethylsulfonylamide, diethylsulfonylamide, n-propylsulfonylamide, isopropylsulfonylamide, N, N-diisopropylsulfonamide, n-butylsulfonamide, tertiary butylsulfonamide, isobutylsulfonamide and secondary butylsulfonamide. A preferred example of "alkylsulfonamide group" is methylsulfonamide group and ethylsulfonamide group.

The term "alkenylsulfonylamino group" means a group in which a hydrogen atom bonded to a nitrogen atom of an amine group is replaced by the above-mentioned "alkenylsulfonyl group". For example, it includes vinylsulfonamide, propenylsulfonamide and the like. Another hydrogen atom bonded to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkynylsulfonylamino group" means a group in which a hydrogen atom bonded to a nitrogen atom of an amine group is replaced by the above-mentioned "alkynylsulfonyl group". For example, it includes ethynylsulfonamide, propynylsulfonamide, and the like. Another hydrogen atom bonded to the nitrogen atom of the amine group may be replaced by the above-mentioned "alkyl group".

The term "alkylimino group" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkyl group". Examples include methylimino, ethylimino, n-propylimino and isopropylimino.

The term "alkenylimino" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkenyl". Examples include vinylimine and n-propyleneimine.

The term "alkynylimino" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkynyl". Examples include ethynylimine and n-propynylimine.

The term "alkylcarbonylimino" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkylcarbonyl". Examples include methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino and isopropylcarbonylimino.

The term "alkenylcarbonylimino" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkenylcarbonyl". Examples include vinylcarbonylimine and n-propenylcarbonylimine.

The term "alkynylcarbonylimino" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkynylcarbonyl". Examples include ethynylcarbonylimino and n-propynylcarbonylimino.

The term "alkoxyimino group" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkoxy group". Examples include methoxyimino, ethoxyimino, n-propoxyimino and isopropoxyimino.

The term "alkenyloxyimino group" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkenyloxy group". Examples include ethyleneoxyimine and n-propyleneoxyimine.

The term "alkynyloxyimino group" means a group in which a hydrogen atom attached to a nitrogen atom of an imino group is replaced by the above-mentioned "alkynyloxy group". Examples include ethynyloxyimine and n-propynyloxyimine.

The term "alkylcarbonyloxy" means a group in which the above-mentioned "alkylcarbonyl" is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tertiary butylcarbonyloxy, isobutylcarbonyloxy and secondary butylcarbonyloxy . A preferred example of "alkylcarbonyloxy" is methylcarbonyloxy and ethylcarbonyloxy.

The term "alkenylcarbonyloxy" means a group in which the above-mentioned "alkenylcarbonyl" is bonded to an oxygen atom. Examples include vinylcarbonyloxy and n-propenylcarbonyloxy.

The term "alkynylcarbonyloxy" means a group in which the above-mentioned "alkynylcarbonyl" is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and n-propynylcarbonyloxy.

The term "alkoxycarbonyl" means a group in which the above-mentioned "alkoxy" is bonded to a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tertiary butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl and n-hexyloxycarbonyl. A preferred example of "alkoxycarbonyl" is methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl.

The term "alkenyloxycarbonyl" means a group in which the above-mentioned "alkenyloxy" is bonded to a carbonyl group. Examples include ethyleneoxycarbonyl and n-propyleneoxycarbonyl.

The term "alkynyloxycarbonyl" means a group in which the above-mentioned "alkynyloxy" is bonded to a carbonyl group. Examples include ethynyloxycarbonyl and n-propynyloxycarbonyl.

The term "alkylmercapto" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by the above-mentioned "alkyl group". Examples include methylmercapto, ethylmercapto, n-propylmercapto and isopropylmercapto.

The term "alkenylthiol" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by the above-mentioned "alkenyl". Examples include vinylmercapto and n-propenylmercapto.

The term "alkynylthio" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by the above-mentioned "alkynyl". Examples include ethynylmercapto and n-propynylmercapto.

The term "alkylsulfinyl" means a group in which the above-mentioned "alkyl" is bonded to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and isopropylsulfinyl.

The term "alkenylsulfinyl" means a group in which the above-mentioned "alkenyl" is bonded to a sulfinyl group. Examples include vinylsulfinyl and n-propenylsulfinyl.

The term "alkynylsulfinyl" means a group in which the above-mentioned "alkynyl" is bonded to a sulfinyl group. Examples include ethynylsulfinyl and n-propynylsulfinyl.

The term "alkylcarbamoyl group" means a group in which a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced by the above-mentioned "alkyl group". For example, it includes methylcarbamoyl, ethylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced by the above-mentioned "alkyl group".

The term "alkenylcarbamoyl" means a group in which a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced by the above-mentioned "alkenyl". For example, it includes vinylcarbamoyl, propenylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced by the above-mentioned "alkyl group".

The term "alkynylaminoformyl" means a group in which a hydrogen atom bonded to a nitrogen atom of an aminoformyl group is replaced by the above-mentioned "alkynyl". For example, it includes ethynylcarbamoyl, propynylcarbamoyl, and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced by the above-mentioned "alkyl group".

The term "alkylsulfamoyl group" means a group in which the hydrogen atom bonded to the nitrogen atom of the sulfamoyl group is replaced by the above-mentioned "alkyl group". For example, it includes methylsulfamoyl, dimethylsulfamoyl, and the like. Another hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced by the above-mentioned "alkyl group".

The term "alkenylsulfamoyl" means a group in which the hydrogen atom bonded to the nitrogen atom of the sulfamoyl group is replaced by the above-mentioned "alkenyl". For example, it includes vinylsulfamoyl, propenylsulfamoyl, and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced by the above-mentioned "alkyl group".

The term "alkynylsulfamoyl" means a group in which the hydrogen atom bonded to the nitrogen atom of the sulfamoyl group is replaced by the above-mentioned "alkynyl". For example, it includes ethynylsulfamoyl, propynylsulfamoyl, and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced by the above-mentioned "alkyl group".

The term "aromatic carbocyclic group" means a cyclic aromatic hydrocarbon group which is a monocyclic ring or a polycyclic ring having two or more rings. Examples include phenyl, naphthyl, anthracenyl and phenanthrenyl. A preferred example of "aromatic carbocyclic group" is phenyl.

The term "aromatic carbocycle" means a cyclic aromatic hydrocarbon ring as a monocyclic ring or a polycyclic ring having two or more rings. Examples include benzene, naphthalene, anthracene and phenanthrene rings. A preferred example of the "aromatic carbocycle" is a benzene ring or a naphthalene ring.

作為單環之非芳族碳環基較佳為C3至C16、更佳C3至C12且更佳C4至C8碳環基。實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基、環癸基、環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基及環己二烯基。 作為具有兩個或更多個環之多環的非芳族碳環基之實例包括二氫茚基、茚基、苊基、四氫萘基及茀基。 The term "non-aromatic carbocyclic group" means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group which is a monocyclic ring or a polycyclic ring having two or more rings. A "non-aromatic carbocyclic group" which is a polycyclic ring having two or more rings includes a condensed ring group, wherein a non-aromatic carbocyclic group which is a monocyclic ring or a polycyclic ring having two or more rings Condensed with the ring of the above-mentioned "aromatic carbocyclic group". In addition, examples of the "non-aromatic carbocyclic group" also include groups having bridges or groups forming spiro rings as follows:

The non-aromatic carbocyclic group which is a monocyclic ring is preferably a C3 to C16, more preferably a C3 to C12 and more preferably a C4 to C8 carbocyclic group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl and cyclohexadienyl. Examples of the polycyclic non-aromatic carbocyclic group having two or more rings include indenyl, indenyl, acenaphthyl, tetrahydronaphthyl and perylene.

作為單環之非芳族碳環較佳為C3至C16、更佳C3至C12且更佳C4至C8碳環基。實例包括環丙烷、環丁烷、環戊烷、環己烷、環庚烷、環辛烷、環壬烷、環癸烷、環丙烯、環丁烯、環戊烯、環己烯、環庚烯及環己二烯。 作為具有兩個或更多個環之多環的非芳族碳環之實例包括茚烷、茚、二氫苊、四氫萘及茀。 The term "non-aromatic carbocycle" means a cyclic saturated hydrocarbon ring or a cyclic unsaturated non-aromatic hydrocarbon ring as a monocyclic ring or a polycyclic ring having two or more rings. The "non-aromatic carbocycle" which is a polycyclic ring having two or more rings includes condensed rings, wherein the non-aromatic carbocyclic ring which is a monocyclic ring or a polycyclic ring having two or more rings is the same as the above-mentioned "aromatic carbocycle". Group carbocycle" ring fusion. In addition, examples of the "non-aromatic carbocycle" also include rings having a bridge or rings forming spiro rings as follows:

The non-aromatic carbocycle which is a monocyclic ring is preferably a C3 to C16, more preferably a C3 to C12 and more preferably a C4 to C8 carbocyclic group. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptane alkenes and cyclohexadiene. Examples of the polycyclic non-aromatic carbocycle having two or more rings include indenes, indenes, acenaphthylenes, tetrahydronaphthalene and terylene.

基、喹啉基、異喹啉基、㖕啉基、呔𠯤基、喹唑啉基、㖠啶基、喹㗁啉基、嘌呤基、喋啶基、苯并咪唑基、苯并異㗁唑基、苯并㗁唑基、苯并㗁二唑基、苯并異噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、三唑并吡啶基、咪唑并噻唑基、吡𠯤并嗒𠯤基、㗁唑并吡啶基及噻唑并吡啶基。 作為具有三個或更多個環之多環的芳族雜環基之實例包括咔唑基、吖啶基、𠮿

基、啡噻𠯤基、啡㗁噻基、啡㗁 𠯤基及二苯并呋喃基。 The term "aromatic heterocyclic group" means an aromatic ring containing one or more same or different heteroatoms independently selected from O, S and N as a single ring or a polycyclic ring having two or more rings base. The "aromatic heterocyclic group" which is a polycyclic ring having two or more rings includes condensed ring groups, wherein the aromatic heterocyclic group which is a monocyclic ring or a polycyclic ring having two or more rings is the same as the above-mentioned The ring fusion of "aromatic carbocyclyl". The aromatic heterocyclic group as a monocyclic ring is preferably a 5-membered to 8-membered ring and more preferably a 5- to 6-membered ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, triazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, Azolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl. Examples of bicyclic aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolyl,

Base, quinolinyl, isoquinolyl, zeolinyl, thiol, quinazolinyl, phenidyl, quinazolyl, purinyl, pteridyl, benzimidazolyl, benzisoxazole benzothiazolyl, benzothiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzene Triazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazolopyridyl, oxazolopyridyl and thiazolopyridyl. Examples of polycyclic aromatic heterocyclic groups having three or more rings include carbazolyl, acridinyl,

phenanthienyl, phenanthyl, phenanthyl, phenanthyl and dibenzofuryl.

、喹啉、異喹啉、㖕啉、呔𠯤、喹唑啉、㖠啶、喹㗁啉、嘌呤、喋啶、苯并咪唑、苯并異㗁唑、苯并㗁唑、苯并㗁二唑、苯并異噻唑、苯并噻唑、苯并噻二唑、苯并呋喃、異苯并呋喃、苯并噻吩、苯并三唑、咪唑吡啶、三唑并吡啶、咪唑并噻唑、吡𠯤嗒𠯤、㗁唑并吡啶及噻唑并吡啶。 作為具有三個或更多個環之多環的芳族雜環之實例包括咔唑、吖啶、𠮿

、啡噻𠯤、啡㗁噻、啡㗁𠯤及二苯并呋喃。 The term "aromatic heterocycle" means an aromatic ring containing one or more same or different heteroatoms independently selected from O, S and N, as a single ring or a polycyclic ring having two or more rings. "Aromatic heterocyclic ring" which is a polycyclic ring having two or more rings includes condensed rings, wherein the aromatic heterocyclic ring which is a monocyclic ring or a polycyclic ring having two or more rings is combined with the above-mentioned "aromatic carbon "ring" ring fusion. The aromatic heterocycle as a monocyclic ring is preferably a 5- to 8-membered ring and more preferably a 5- or 6-membered ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazole, pyrimidine, pyridazole, triazole, triazole, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole azole. Examples of aromatic heterocycles that are bicyclic include indole, isoindole, indazole, indole

, quinoline, isoquinoline, phenoline, 呔𠯤, quinazoline, phenidine, quinzoline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole , benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyridoxetine , oxazolopyridine and thiazolopyridine. Examples of polycyclic aromatic heterocycles having three or more rings include carbazole, acridine,

, phenothiophene 𠯤, morphine 㗁thiophene, morphine 㗁𠯤 and dibenzofuran.

作為單環之非芳族雜環基較佳為3員至8員且更佳為5員至6員環。實例包括二㗁烷基、硫

基、氧

基、氧呾基、氧雜硫㖦基、吖呾基、噻𠮿基、噻唑啶基、吡咯啶基、吡咯啉基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、哌啶基、哌𠯤基、𠰌啉基、N-𠰌啉基、硫代𠰌啉基(thiomorpholinyl)、N-硫代𠰌啉基(thiomorpholino)、二氫吡啶基、四氫吡啶基、四氫呋喃基、四氫哌喃基、二氫噻唑基、四氫異噻唑基、二氫㗁𠯤基、六氫氮呯基、四氫二氮呯基、四氫嗒𠯤基、六氫嘧啶基、二氧雜環戊烷基(dioxolanyl)、二㗁𠯤基、氮丙啶基、二氧炔基(dioxolynyl)、氧雜環庚烷基、硫㖦基、噻喃基及噻𠯤基。 作為具有兩個或更多個環之多環的非芳族雜環基之實例包括吲哚啉基、異吲哚啉基、𠳭烷基及異𠳭烷基。 The term "non-aromatic heterocyclic group" means a non-aromatic group containing one or more same or different heteroatoms independently selected from O, S and N, either as a single ring or as a polycyclic ring having two or more rings. family ring group. "Non-aromatic heterocyclic group" as a polycyclic ring having two or more rings includes the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group" The above-mentioned non-aromatic heterocyclic group whose ring is fused. The "non-aromatic heterocyclic group" which is a polycyclic ring having two or more rings includes ring-fused rings of the above-mentioned "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group" which are monocyclic Or a polycyclic aromatic heterocyclic group having two or more rings. In addition, examples of the "non-aromatic heterocyclic group" also include groups having bridges or groups forming spiro rings as follows:

The non-aromatic heterocyclic group which is a monocyclic ring is preferably a 3-membered to 8-membered ring and more preferably a 5-membered to 6-membered ring. Examples include diazanyl, sulfur

base, oxygen

Base, oxo group, oxathiol group, acridyl group, thiazyl group, thiazolidinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolinyl group, pyrazolinyl group, Piperidinyl, piperyl, thiol, N-thiol, thiomorpholinyl, N-thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl , Tetrahydropyranyl, Dihydrothiazolyl, Tetrahydroisothiazolyl, Dihydropyrazyl, Hexahydroazanyl, Tetrahydrodiazoyl, Tetrahydropyridyl, Hexahydropyrimidinyl, Dioxo Dioxolanyl, dioxolyl, aziridinyl, dioxolynyl, oxepanyl, thioxanyl, thiopyranyl and thiopyryl. Examples of the polycyclic non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, indolinyl, and isoindolinyl.

、氧

、氧呾、氧雜硫㖦、吖呾、噻𠮿、噻唑啶、吡咯啶、吡咯啉、咪唑啶、咪唑啉、吡唑啶、吡唑啉、哌啶、哌𠯤、吡啶酮、𠰌啉、硫代𠰌啉、二氫吡啶、四氫吡啶、四氫呋喃、四氫哌喃、二氫噻唑、四氫噻唑、四氫異噻唑、二氫㗁𠯤、六氫氮呯、四氫二氮呯、四氫嗒𠯤、六氫嘧啶、二氧雜環戊烷、二㗁𠯤、氮丙啶、二氧炔、氧雜環庚烷、硫㖦、噻喃及噻𠯤。 作為具有兩個或更多個環之多環的非芳族雜環之實例包括吲哚啉、異吲哚啉、𠳭烷及異𠳭烷。 The term "non-aromatic heterocycle" means a cyclic non-aromatic ring containing one or more same or different heteroatoms selected from O, S and N as a single ring or as a polycyclic ring having two or more rings ring. "Non-aromatic heterocycle" which is a polycyclic ring having two or more rings includes ring condensed with the above-mentioned "aromatic carbocycle", "non-aromatic carbocycle" and/or "aromatic heterocycle" The non-aromatic heterocycle mentioned above. In addition, the "non-aromatic heterocycle" also includes a ring having a bridge or a ring forming a spiro ring. The non-bridged non-aromatic heterocyclic ring is preferably a 3- to 8-membered ring, more preferably a 4- to 8-membered ring, and more preferably a 5- or 6-membered ring. The bridged non-aromatic heterocycle is preferably a 6- to 10-membered ring and more preferably an 8- or 9-membered ring. Herein, the number of members means the number of all ring atoms bridging the non-aromatic heterocycle. The non-aromatic heterocyclic ring which is a monocyclic ring is preferably a 3- to 8-membered ring and more preferably a 5- or 6-membered ring. Examples include dioxane, sulfur

,oxygen

, Oxygen, Oxathio, Acridine, Thiazolidine, Thiazolidine, Pyrrolidine, Pyrroline, Imidazolidine, Imidazoline, Pyrazolidine, Pyrazolidine, Piperidine, Piperone, Pyridone, Pyrroline, Thiothioline, Dihydropyridine, Tetrahydropyridine, Tetrahydrofuran, Tetrahydropyran, Dihydrothiazole, Tetrahydrothiazole, Tetrahydroisothiazole, Dihydropyridine, Hexahydronitrogen, Tetrahydrodiazepine, Four Hydrogen pyrimidine, hexahydropyrimidine, dioxolane, dioxin, aziridine, dioxyalkyne, oxepane, thiophene, thiopyran, and thiophene. Examples of the non-aromatic heterocyclic ring as a polycyclic ring having two or more rings include indoline, isoindoline, indoline and isoindoline.

The term "aromatic carbocyclyloxy" means a group in which an "aromatic carbocycle" is bonded to an oxygen atom. Examples include phenoxy and naphthoxy.

The term "non-aromatic carbocyclyloxy" means a group in which a "non-aromatic carbocycle" is bonded to an oxygen atom. Examples include cyclopropoxy, cyclohexyloxy and cyclohexenyloxy.

The term "aromatic heterocyclyloxy" means a group in which an "aromatic heterocycle" is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.

The term "non-aromatic heterocyclyloxy" means a group in which a "non-aromatic heterocycle" is bonded to an oxygen atom. Examples include piperidinyloxy and tetrahydrofuranyloxy.

The term "aromatic carbocyclylcarbonyl" means a group in which an "aromatic carbocycle" is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.

The term "non-aromatic carbocyclylcarbonyl" means a group in which a "non-aromatic carbocycle" is bonded to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl and cyclohexenylcarbonyl.

The term "non-aromatic carbocyclylcarbonyloxy" means a group in which the "non-aromatic carbocyclylcarbonyl" is bonded to an oxygen atom. Examples include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy and cyclohexenylcarbonyloxy.

The term "aromatic heterocyclic carbonyl" means a group in which an "aromatic heterocyclic ring" is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.

The term "non-aromatic heterocyclic carbonyl" means a group in which a "non-aromatic heterocyclic ring" is bonded to a carbonyl group. Examples include piperidinylcarbonyl and tetrahydrofurylcarbonyl.

The term "aromatic carbocyclyloxycarbonyl" means a group in which the "aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include phenoxycarbonyl and naphthoxycarbonyl.

The term "non-aromatic carbocyclyloxycarbonyl" means a group wherein the "non-aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include cyclopropoxycarbonyl, cyclohexyloxycarbonyl and cyclohexenyloxycarbonyl.

The term "aromatic heterocyclyloxycarbonyl" means a group in which the "aromatic heterocyclyloxy" is bonded to a carbonyl group. Examples include pyridyloxycarbonyl and oxazolyloxycarbonyl.

The term "non-aromatic heterocyclyloxycarbonyl" means a group in which the "non-aromatic heterocyclyloxy" is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl and tetrahydrofuranyloxycarbonyl.

。 The term "aromatic carbocyclylalkoxy" means an alkoxy group substituted with one or more "aromatic carbocyclyl" groups described above. Examples include benzyloxy, phenethoxy, phenyl-n-propoxy, benzyloxy, trityloxy, naphthylmethoxy and groups of the formula:

.

。 The term "non-aromatic carbocyclylalkoxy" means an alkoxy group substituted with one or more "non-aromatic carbocyclyl" groups described above. "Non-aromatic carbocyclylalkoxy" also includes "non-aromatic carbocyclylalkoxy" in which the alkyl moiety is substituted with the above-mentioned "aromatic carbocyclyl". Examples include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and groups of the formula:

.

。 The term "aromatic heterocyclylalkoxy" means an alkoxy group substituted with one or more "aromatic heterocyclyl" described above. "Aromatic heterocyclylalkoxy" also includes "aromatic heterocyclylalkoxy" in which the alkyl moiety is substituted by the above-mentioned "aromatic carbocyclyl" and/or "non-aromatic carbocyclyl". Examples include pyridylmethoxy, furylmethoxy, imidazolylmethoxy, indolylmethoxy, benzothienylmethoxy, oxazolylmethoxy, isoxazolylmethoxy, Thiazolylmethoxy, isothiazolylmethoxy, pyrazolylmethoxy, isopyrazolylmethoxy, pyrrolidinylmethoxy, benzozizolylmethoxy and groups of the following formula:

.

。 The term "non-aromatic heterocyclylalkoxy" means an alkoxy group substituted with one or more "non-aromatic heterocyclyl" as described above. "Non-aromatic heterocyclylalkoxy" also includes "non-aromatic heterocyclyl" in which the alkyl part is substituted by the above-mentioned "aromatic carbocyclyl", "non-aromatic carbocyclyl" and/or "aromatic heterocyclyl". Group heterocyclylalkoxy". Examples include tetrahydropyranylmethoxy, metholinylmethoxy, metholinylethoxy, piperidinylmethoxy, piperylmethoxy and groups of the formula:

.

。 The term "aromatic carbocyclylalkoxycarbonyl" means an alkoxycarbonyl group substituted with one or more "aromatic carbocyclyl" described above. Examples include benzyloxycarbonyl, phenethoxycarbonyl, phenyl-n-propoxycarbonyl, diphenylmethoxycarbonyl, trityloxycarbonyl, naphthylmethoxycarbonyl and groups of the formula:

.

。 The term "non-aromatic carbocyclylalkoxycarbonyl" means an alkoxycarbonyl group substituted with one or more of the "non-aromatic carbocyclyl" described above. "Non-aromatic carbocyclylalkoxycarbonyl" also includes "non-aromatic carbocyclylalkoxycarbonyl" in which the alkyl moiety is substituted with the above-mentioned "aromatic carbocyclyl". Examples include cyclopropylmethoxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl and groups of the formula:

.

。 The term "aromatic heterocyclylalkoxycarbonyl" means an alkoxycarbonyl group substituted with one or more "aromatic heterocyclic groups" described above. "Aromatic heterocyclic alkoxycarbonyl" also includes "aromatic heterocyclic alkoxycarbonyl" in which the alkyl part is substituted by the above-mentioned "aromatic carbocyclic group" and/or "non-aromatic carbocyclic group" . Examples include pyridylmethoxycarbonyl, furylmethoxycarbonyl, imidazolylmethoxycarbonyl, indolylmethoxycarbonyl, benzothienylmethoxycarbonyl, oxazolylmethoxycarbonyl, isozolylmethoxycarbonyl, Azolylmethoxycarbonyl, thiazolylmethoxycarbonyl, isothiazolylmethoxycarbonyl, pyrazolylmethoxycarbonyl, isopyrazolylmethoxycarbonyl, pyrrolidinylmethoxycarbonyl, benzo Azolylmethoxycarbonyl and groups of the following formula:

.

。 The term "non-aromatic heterocyclic alkoxycarbonyl" means an alkoxycarbonyl group substituted with one or more "non-aromatic heterocyclic groups" described above. "Non-aromatic heterocyclic alkoxycarbonyl" also includes "non-aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group" in which the alkyl part is Aromatic heterocyclylalkoxycarbonyl". Examples include tetrahydropyranylmethoxycarbonyl, metholinylethoxycarbonyl, piperidinylmethoxycarbonyl, piperylmethoxycarbonyl and groups of the formula:

.

The term "aromatic carbocyclylalkylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "aromatic carbocyclylalkyl group". Examples include benzylamine, phenethylamine, phenylpropylamine, benzhydrylamine, tritylamine, naphthylmethylamine and benzhydrylamine.

The term "non-aromatic carbocyclylalkylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "non-aromatic carbocyclylalkyl group". Examples include cyclopropylmethylamine, cyclobutylmethylamine, cyclopentylmethylamine and cyclohexylmethylamine.

The term "aromatic heterocyclylalkylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amine group are replaced by the above-mentioned "aromatic heterocyclylalkyl group". Examples include pyridylmethylamino, furylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothienylmethylamino, zozolylmethylamino, isozolyl Azolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino and benzoxazole base methylamine.

The term "non-aromatic heterocyclic alkylamino group" means a group in which one or two hydrogen atoms attached to nitrogen atoms of an amino group are replaced by the above-mentioned "non-aromatic heterocyclic alkyl group". Examples include tetrahydropyranylmethylamine, metholinylethylamine, piperidinylmethylamine and piperidylmethylamine.

The term "aromatic carbocyclylthiol" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by an "aromatic carbocycle". Examples include phenylmercapto and naphthylmercapto.

The term "non-aromatic carbocyclylthiol" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by a "nonaromatic carbocycle". Examples include cyclopropylmercapto, cyclohexylmercapto and cyclohexenylmercapto.

The term "aromatic heterocyclic mercapto" means a group in which a hydrogen atom attached to a sulfur atom of a mercapto group is replaced by an "aromatic heterocyclic ring". Examples include pyridylthio and azolylthio.

The term "non-aromatic heterocyclic mercapto" means a group in which the hydrogen atom attached to the sulfur atom of the mercapto group is replaced by a "non-aromatic heterocyclic ring". Examples include piperidinylmercapto and tetrahydrofurylmercapto.

The term "non-aromatic carbocyclylsulfonyl" means a group in which a "non-aromatic carbocycle" is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl and cyclohexenylsulfonyl.

The term "aromatic carbocyclylsulfonyl" means a group in which an "aromatic carbocycle" is bonded to a sulfonyl group. Examples include phenylsulfonyl and naphthylsulfonyl.

The term "aromatic heterocyclic sulfonyl group" means a group in which an "aromatic heterocyclic ring" is bonded to a sulfonyl group. Examples include pyridylsulfonyl and oxazolylsulfonyl.

The term "non-aromatic heterocyclic sulfonyl group" means a group in which a "non-aromatic heterocyclic ring" is bonded to a sulfonyl group. Examples include piperidinylsulfonyl and tetrahydrofuranylsulfonyl.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , X, A preferred embodiment of Y, m and n. Compounds having any possible combination of those described below are preferred.

R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.

Preferably, R ¹ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. More preferably, R ¹ is a hydrogen atom, halogen or substituted or unsubstituted alkyl. Especially preferably, R ¹ is a hydrogen atom.

When R ¹ is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amine, cyano, alkoxy, alkylamine and the like. When R ¹ is a substituted group, another preferred substituent on the substituted group is selected from halogen and the like.

Preferably, R ² is a hydrogen atom, halogen, cyano or substituted or unsubstituted alkyl. Further preferably, R ² is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. Especially preferably, R ² is a hydrogen atom or a halogen.

When R2 is a substituted group, preferred substituents ^on the substituted group are selected from halogen, hydroxyl, amine, cyano, alkoxy, alkylamine and the like. When R2 is a substituted group, another preferred substituent ^on the substituted group is selected from halogen and the like.

Preferably, R ³ is a hydrogen atom, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. Further preferably, R ³ is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. Especially preferably, R ³ is a hydrogen atom or a halogen.

When ^R3 is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, amine, cyano, alkoxy, alkylamine and the like. When ^R3 is a substituted group, another preferred substituent on the substituted group is selected from halogen and the like.

Preferably, R ⁴ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. Further preferably, R ⁴ is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. Especially preferably, R ⁴ is a hydrogen atom.

When R4 is a substituted group, preferred substituents ^on the substituted group are selected from halogen, hydroxyl, amine, cyano, alkoxy, alkylamine and the like. When R ⁴ is a substituted group, another preferred substituent on the substituted group is selected from halogen and the like.

R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Preferably, R ⁵ is halogen or substituted or unsubstituted alkyl. Further preferably, R ⁵ is a substituted or unsubstituted alkyl group.

When R ⁵ is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, amine, cyano, alkoxy, alkylamine and the like. When R ⁵ is a substituted group, another preferred substituent on the substituted group is selected from halogen and the like.

R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted Substituted alkynyl, the limitation is that R ⁶ , R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time.

Preferably, R ⁶ is a hydrogen atom or a halogen. Further preferably, R ⁶ is a hydrogen atom.

Preferably, R ⁷ is a hydrogen atom or a halogen. Further preferably, R ⁷ is halogen.

Preferably, R ⁸ is a hydrogen atom or a halogen. Further preferably, R ⁸ is a hydrogen atom.

Preferably, R ⁹ is a hydrogen atom or a halogen. Further preferably, R ⁹ is a hydrogen atom.

Embodiments wherein R ⁷ is halogen and R ⁶ , R ⁸ and R ⁹ are hydrogen atoms are also preferred.

Embodiments wherein R ⁶ is halogen and R ⁷ , R ⁸ and R ⁹ are hydrogen atoms are also preferred.

Embodiments wherein R ⁷ and R ⁸ are each independently halogen and R ⁶ and R ⁹ are hydrogen atoms are also preferred.

Embodiments wherein R ⁶ and R ⁷ are each independently halogen and R ⁸ and R ⁹ are hydrogen atoms are also preferred.

Embodiments wherein R ⁷ and R ⁹ are each independently halogen and R ⁶ and R ⁸ are hydrogen atoms are also preferred.

When R6 is a substituted group, preferred substituents ^on the substituted group are selected from halogen, hydroxy, alkoxy and the like. When R6 is a substituted group, another preferred substituent ^on the substituted group is selected from halogen.

When R ⁷ is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, alkoxy and the like. When R ⁷ is a substituted group, another preferred substituent on the substituted group is selected from halogen.

When ^R8 is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, alkoxy and the like. When ^R8 is a substituted group, another preferred substituent on the substituted group is selected from halogen.

When R ⁹ is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, alkoxy and the like. When R ⁹ is a substituted group, another preferred substituent on the substituted group is selected from halogen.

X is CH or N.

Y is CH or N.

Embodiments wherein X is N and Y is N are also preferred.

Embodiments wherein X is N and Y is CH are also preferred.

Embodiments wherein X is CH and Y is N are also preferred.

m is 0, 1, 2, 3 or 4. Preferably, m is 0, 1 or 2. Further preferably, m is 1 or 2. Particularly preferably, m is 1.

較佳為由下式表示之基團：

。 In the case where m is 1, the group represented by the following formula in formula (I):

Preferred is a group represented by the following formula:

.

較佳為由下式表示之基團：

。 In the case where m is 2, the group represented by the following formula in formula (I):

Preferred is a group represented by the following formula:

.

Each R ¹⁰ is independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Preferably, each R ¹⁰ is independently halogen or substituted or unsubstituted alkyl. Further preferably, each of R ¹⁰ is independently substituted or unsubstituted alkyl.

When R ¹⁰ is a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, amine, cyano, alkoxy, alkylamine and the like.

R ¹¹ is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy , substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, or pentafluorothio. Preferably, R ¹¹ is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. Further preferably, R ¹¹ is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. More preferably, R ¹¹ is substituted or unsubstituted alkoxy, including trihaloalkyloxy (such as OCF ₃ ).

When R is a substituted group, preferred substituents ^on the substituted group are selected from halogen, hydroxyl, amine, alkoxy, alkylamine, non-aromatic carbocyclic groups and Similar groups. When R ¹¹ is a substituted group, another preferred substituent on the substituted group is selected from halogen and the like.

Each ^R12 is independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy. Preferably, each R ¹² is independently halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.

When R ¹² is a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

n is 0, 1, 2, 3 or 4. Preferably, n is 0, 1 or 2. Further preferably, n is 0 or 1. Particularly preferably, n is 0.

Preferred combinations of substituents of compounds represented by formula (I) include the following 1) to 6): 1) the following compounds: wherein R ¹ and R ⁴ are hydrogen atoms; R ² is halogen; R ³ is hydrogen atom; R ⁵ is a substituted or unsubstituted alkyl group; R ⁶ , R ⁸ and R ⁹ are hydrogen atoms; R ⁷ is halogen; X is N; Y is N; m is 1; R ¹⁰ is substituted or unsubstituted R ¹¹ is a substituted or unsubstituted alkoxy group; n is 0; 2) the following compounds: wherein R ¹ and R ⁴ are hydrogen atoms; R ² is a halogen; R ³ is a hydrogen atom; R ⁵ is substituted or unsubstituted alkyl; R ⁷ , R ⁸ and R ⁹ are hydrogen atoms; R ⁶ is halogen; X is CH; Y is N; m is 0; R ¹¹ is substituted or unsubstituted Alkyl; n is 0; 3) The following compounds: wherein R ¹ and R ⁴ are hydrogen atoms; R ² is hydrogen atom; R ³ is halogen; R ⁵ is substituted or unsubstituted alkyl; R ⁷ , R ⁸ and R ⁹ are hydrogen atoms; R ⁶ is halogen; X is CH; Y is N; m is 0; R ¹¹ is substituted or unsubstituted alkyl; n is 0; 4) the following compounds: wherein R ¹ and R ⁴ is a hydrogen atom; R ² is a hydrogen atom; R ³ is a halogen; R ⁵ is a substituted or unsubstituted alkyl group; R ⁶ , R ⁸ and R ⁹ are hydrogen atoms; R ⁷ is a halogen; X is N; Y is N; m is 1; R ¹⁰ is substituted or unsubstituted alkyl; R ¹¹ is substituted or unsubstituted alkoxy; n is 0; 5) the following compounds: wherein R ¹ and R ⁴ is a hydrogen atom; R ² is a halogen; R ³ is a hydrogen atom; R ⁵ is a substituted or unsubstituted alkyl group; R ⁶ , R ⁸ and R ⁹ are hydrogen atoms; R ⁷ is a halogen; X is N ; Y is N; m is 2; R ¹⁰ is independently substituted or unsubstituted alkyl; R ¹¹ is substituted or unsubstituted alkoxy; n is 0; 6) the following compounds: wherein R ¹ and R ⁴ are hydrogen atoms; R ² is a substituted or unsubstituted alkyl group; R ³ is a hydrogen atom; R ⁵ is a substituted or unsubstituted alkyl group; R ⁶ , R ⁸ and R ⁹ are hydrogen atom; R ⁷ is halogen; X is N; Y is N; m is 1; R ¹⁰ is substituted or unsubstituted alkyl; R ¹¹ is substituted or unsubstituted alkoxy; n is 0.

或其醫藥學上可接受之鹽尤佳地為選自由以下組成之群的化合物：

或其醫藥學上可接受之鹽。 Compounds represented by formula (I):

Or a pharmaceutically acceptable salt thereof is preferably a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Any one or more of the compounds of the present invention (compound represented by formula (I), clarithromycin, azithromycin or clofazimine) may be in the form of a pharmaceutically acceptable salt, if desired. Pharmaceutically acceptable salts of the compounds include, for example, compounds with alkali metals (e.g., lithium, sodium, or potassium), alkaline earth metals (e.g., calcium or barium), magnesium, transition metals (e.g., zinc or iron), ammonia, organic bases (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, or quinoline) or salts of amino acids, or with inorganic acids (e.g., hydrochloric, sulfuric, nitric, carbonic, hydrobromic, phosphoric, or hydriodic) or organic acids (e.g., formic, acetic, propionic, trifluoroacetic, citric, lactic, tartaric, oxalic, maleic dioic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid). Specifically, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, and the like are included. Such salts can be formed by usual methods.

Compounds of formula (I) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, enantiomers isomers or rotamers), racemates or mixtures thereof.

One or more hydrogen, carbon and/or other atoms in the compounds of formula (I) may be replaced by isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P , ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ³⁶ Cl. Compounds of formula (I) include such isotopically substituted compounds. The above-mentioned isotope-substituted compounds are suitable for use as pharmaceuticals and include all radiolabeled compounds of the compounds of formula (I). The present invention covers the "radiolabeling method" in the manufacture of "radiolabeled compounds", and the "radiolabeled compounds" are suitable for studies on the pharmacokinetics of metabolic drugs, studies on binding assays and/or diagnostic tools.

Radiolabeled compounds of compounds of formula (I) can be prepared using methods well known in the field of the invention. For example, tritiated compounds of formula (I) can be prepared by introducing tritium into a compound of formula (I) via a catalytic dehalogenation reaction using tritium. This method involves reacting a suitable halogenated precursor of a compound of formula (I) with tritium gas in the presence of a suitable catalyst such as Pd/C and in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". ¹⁴ C-labeled compounds can be prepared by using starting materials having ¹⁴ C.

A compound of formula (I) or a pharmaceutically acceptable salt thereof may form solvates (eg, hydrates), co-crystals and/or crystalline polymorphs. The present invention encompasses their various solvates, co-crystals and crystalline polymorphs. "Solvates" can be those in which any number of solvent molecules (eg, water molecules) are coordinated to the compound of formula (I). When the compound of formula (I) or a pharmaceutically acceptable salt thereof is allowed to stand in the atmosphere, the compound can absorb water, thereby causing attachment of the adsorbed water or formation of a hydrate. Recrystallization of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in crystalline polymorphs. "Co-crystal" means that the compound of formula (I) or a salt thereof and the counter molecule exist in the same crystal lattice, and it may be formed by any number of counter molecules.

The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof can form a prodrug. The present invention also encompasses such various prodrugs. Prodrugs are derivatives of compounds of the present invention having chemically or metabolically decomposable groups, and compounds that are converted into pharmaceutically active compounds of the present invention through solvolysis or under physiological conditions in vivo. Prodrugs include compounds converted into compounds of formula (I) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo; compounds converted into compounds of formula (I) through hydrolysis of gastric acid, etc.; and the like. Methods for selecting and preparing suitable prodrug derivatives are described eg in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have some activity.

When the compound of formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, the prodrug includes, for example, a compound having a hydroxyl group and a suitable halide acyl group, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl Acyl acid anhydrides and mixed acid anhydrides or acyloxy derivatives and sulfonyloxy derivatives prepared by reacting with a condensing agent. These include, for example, _CH3COO- , C2H5COO-, tert- _BuCOO- , _C15H31COO- , _PhCOO- , (m _{- NaOOCPh} )COO-, _{NaOOCCH2CH2COO-} , _CH3 CH(NH ₂ )COO-, CH ₂ N(CH ₃ ) ₂ COO-, CH ₃ SO ₃ -, CH ₃ CH ₂ SO ₃ -, CF ₃ SO ₃ -, CH ₂ FSO ₃ -, CF ₃ CH ₂ SO ₃ -, p-CH ₃ O-PhSO ₃ -, PhSO ₃ -, and p-CH ₃ PhSO ₃ -.

The term "pharmaceutically acceptable" means not prophylactically or therapeutically harmful.

General procedures for the synthesis of compounds of the invention are described below. The starting materials and reactants used in this synthesis are commercially available or can be synthesized using commercially available compounds according to methods well known in the art. In addition, extraction, purification, and the like can be performed according to methods practiced in this art. In all of the following steps, when there are substituents that hinder the reaction (for example, hydroxyl, mercapto, amino, formyl, carbonyl, carboxyl), advance through Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons, hereinafter referred to as the method described in document A) to protect the substituent, and the protecting group can be removed at the desired stage. In addition, in all steps, the order of steps to be carried out may be appropriately changed, and each intermediate may be isolated and used in the next step. The proprietors in the reaction time, reaction temperature, solvent, reagent, protecting group, etc. are only illustrative and not limiting as long as they do not adversely affect the reaction.

For example, the compounds represented by formula (I) of the present invention can be produced according to the general procedures as described below. In addition, the compounds of the present invention can be prepared according to other methods based on knowledge in organic chemistry.

其中 PG為胺基保護基，諸如Boc、Cbz等，R ^a1為鹵素、三氟甲磺酸根、九氟丁磺酸根、甲磺酸根或甲苯磺酸根，其他符號如上文所定義。 使化合物a1在存在鹼之情況下與化合物a2反應以獲得化合物a3。 溶劑之實例包括甲苯、DMF、DMA、四氫呋喃、乙醇、水、甲苯、乙腈、1,4-二㗁烷及其類似者，且此等溶劑可單獨使用或以組合形式使用。 鹼之實例包括三級丁醇鉀、氫化鈉、碳酸鉀、碳酸銫、三乙胺、二異丙基乙胺、DBU及其類似者。鹼之量可為化合物a1之1至10莫耳當量，較佳1至5莫耳當量。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a3

Wherein PG is an amine protecting group, such as Boc, Cbz, etc., R ^a1 is halogen, trifluoromethanesulfonate, nonafluorobutanesulfonate, methanesulfonate or toluenesulfonate, and other symbols are as defined above. Compound a1 is reacted with compound a2 in the presence of a base to obtain compound a3. Examples of the solvent include toluene, DMF, DMA, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, and the like, and these solvents may be used alone or in combination. Examples of bases include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a1. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a5可藉由在使化合物a3與去保護劑反應之後，在存在鈀、配位體及鹼之情況下與化合物a4反應來獲得。 用於去保護反應之反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 去保護劑之實例包括鹽酸/乙酸乙酯、甲磺酸、三氟乙酸、硫酸、碘基三甲基矽烷、三氯化鋁、溴兒茶酚硼烷、氯化三甲基矽基、三氟甲磺酸三甲基矽基酯及其類似者。去保護劑之量可為化合物a4之1至100莫耳當量，較佳1至50莫耳當量。 鈀之實例包括乙酸鈀、Pd(PPh ₃) ₄、PdCl ₂(PPh ₃) ₂、Pd ₂(dba) ₃及其類似者。鈀之量可為化合物a4之0.01至5莫耳當量，較佳0.01至1莫耳當量。 配位體之實例包括2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯二苯、二環己基-[2-(2,4,6-三異丙基苯基)苯基]膦、(9,9-二甲基-9H-𠮿

-4,5-二基)雙(二苯基膦)及其類似者。配位體之量可為化合物a3之0.01至5莫耳當量，較佳0.01至1莫耳當量。 鹼之實例包括碳酸銫、碳酸鉀、碳酸鈉、三級丁醇鉀、三級丁醇鈉及其類似者。鹼之量可為化合物a4之1至10莫耳當量，較佳1至5莫耳當量。 反應溶劑之實例包括甲醇、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、四氫呋喃、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a5

wherein each symbol is as defined above. Compound a5 can be obtained by reacting compound a4 in the presence of palladium, a ligand and a base after reacting compound a3 with a deprotecting agent. Examples of reaction solvents used in the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and and the like, and these solvents may be used alone or in combination. Examples of deprotecting agents include hydrochloric acid/ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl chloride, Trimethylsilyl fluoromethanesulfonate and the like. The amount of the deprotecting agent can be 1 to 100 molar equivalents of compound a4, preferably 1 to 50 molar equivalents. Examples of palladium include palladium acetate, Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ and the like. The amount of palladium can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalent. Examples of ligands include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-tris Isopropylphenyl)phenyl]phosphine, (9,9-dimethyl-9H-𠮿

-4,5-diyl)bis(diphenylphosphine) and the like. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a3, preferably 0.01 to 1 molar equivalent. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a4. Examples of the reaction solvent include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like , and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a6可藉由在存在鈀、配位體及鹼之情況下與化合物a2及化合物a4反應來獲得。 鈀之實例包括乙酸鈀、Pd(PPh ₃) ₄、PdCl ₂(PPh ₃) ₂、Pd ₂(dba) ₃及其類似者。鈀之量可為化合物a2之0.01至5莫耳當量，較佳0.01至1莫耳當量。 配位體之實例包括2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯二苯、二環己基-[2-(2,4,6-三異丙基苯基)苯基]膦、(9,9-二甲基-9H-𠮿

-4,5-二基)雙(二苯基膦)及其類似者。配位體之量可為化合物a2之0.01至5莫耳當量，較佳0.01至1莫耳當量。 鹼之實例包括碳酸銫、碳酸鉀、碳酸鈉、三級丁醇鉀、三級丁醇鈉及其類似者。鹼之量可為化合物a2之1至10莫耳當量，較佳1至5莫耳當量。 反應溶劑之實例包括甲醇、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、四氫呋喃、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a6

wherein each symbol is as defined above. Compound a6 can be obtained by reacting with compound a2 and compound a4 in the presence of palladium, a ligand and a base. Examples of palladium include palladium acetate, Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ and the like. The amount of palladium can be 0.01 to 5 molar equivalents of compound a2, preferably 0.01 to 1 molar equivalent. Examples of ligands include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-tris Isopropylphenyl)phenyl]phosphine, (9,9-dimethyl-9H-𠮿

-4,5-diyl)bis(diphenylphosphine) and the like. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a2, preferably 0.01 to 1 molar equivalent. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a2. Examples of the reaction solvent include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like , and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a5可藉由在使化合物a6與去保護劑反應之後，在存在鹼之情況下與化合物a1反應來獲得。 用於去保護反應之反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 去保護劑之實例包括鹽酸/乙酸乙酯、甲磺酸、三氟乙酸、硫酸、碘基三甲基矽烷、三氯化鋁、溴兒茶酚硼烷、氯化三甲基矽基、三氟甲磺酸三甲基矽基酯及其類似者。去保護劑之量可為化合物a1之1至100莫耳當量，較佳1至50莫耳當量。 溶劑之實例包括甲苯、DMF、DMA、二甲亞碸、四氫呋喃、乙醇、水、甲苯、乙腈、1,4-二㗁烷及其類似者，且此等溶劑可單獨使用或以組合形式使用。 鹼之實例包括三級丁醇鉀、氫化鈉、碳酸鉀、碳酸銫、三乙胺、二異丙基乙胺、DBU及其類似者。鹼之量可為化合物a1之1至10莫耳當量，較佳1至5莫耳當量。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a5

wherein each symbol is as defined above. Compound a5 can be obtained by reacting compound a6 with a deprotecting agent and then reacting with compound a1 in the presence of a base. Examples of reaction solvents used in the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and and the like, and these solvents may be used alone or in combination. Examples of deprotecting agents include hydrochloric acid/ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl chloride, Trimethylsilyl fluoromethanesulfonate and the like. The amount of the deprotecting agent can be 1 to 100 molar equivalents of compound a1, preferably 1 to 50 molar equivalents. Examples of solvents include toluene, DMF, DMA, dimethylsulfoxide, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, and the like, and these solvents may be used alone or in combination. Examples of bases include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a1. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a7可藉由使化合物a5與還原劑反應來獲得。 反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、乙酸、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 還原劑之實例包括氫氣與Pd碳、氫氣與Pd(OH) ₂、硼氫化鈉與NiCl ₂(H ₂O) ₆、氫化鋁鋰及其類似者。還原劑之量可為化合物a5之1至100莫耳當量，較佳1至10莫耳當量。 反應溫度可為0℃至200℃，較佳為0℃至100℃。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a7

wherein each symbol is as defined above. Compound a7 can be obtained by reacting compound a5 with a reducing agent. Examples of the reaction solvent include ethyl acetate, water, methylene chloride, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, and the like, And these solvents may be used alone or in combination. Examples of reducing agents include hydrogen and Pd carbon, hydrogen and Pd(OH) ₂ , sodium borohydride and NiCl ₂ (H ₂ O) ₆ , lithium aluminum hydride, and the like. The amount of the reducing agent can be 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents to compound a5. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中 R ^a2為鹵素、三氟甲磺酸根、九氟丁磺酸根、甲磺酸根、甲苯磺酸根、

酸(bornic acid)或

酸根(boronate)，R ^a3為三氟甲磺酸根、九氟丁磺酸根、甲磺酸根、甲苯磺酸根、

酸或

酸根，其他符號如上文所定義。 使化合物a8在存在鈀及鹼之情況下與a9反應以獲得化合物a10。 鈀之實例包括乙酸鈀、Pd(PPh ₃) ₄、PdCl ₂(PPh ₃) ₂、Pd ₂(dba) ₃、PdCl ₂(dppf)及其類似者。鈀之量可為化合物a8之0.01至5莫耳當量，較佳0.01至1莫耳當量。 鹼之實例包括碳酸銫、碳酸鉀、碳酸鈉及其類似者。鹼之量可為化合物a8之1至10莫耳當量，較佳1至5莫耳當量。 反應溶劑之實例包括水、DMF、DMA、四氫呋喃、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a10

^Wherein R is halogen, trifluoromethanesulfonate, nonafluorobutanesulfonate, methanesulfonate, toluenesulfonate,

Acid (bornic acid) or

Boronate, R ^a3 is trifluoromethanesulfonate, nonafluorobutanesulfonate, methanesulfonate, toluenesulfonate,

sour or

Acid group, other symbols are as defined above. Compound a8 is reacted with a9 in the presence of palladium and a base to obtain compound a10. Examples of palladium include palladium acetate, Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ , PdCl ₂ (dppf), and the like. The amount of palladium can be 0.01 to 5 molar equivalents of compound a8, preferably 0.01 to 1 molar equivalent. Examples of bases include cesium carbonate, potassium carbonate, sodium carbonate and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a8. Examples of the reaction solvent include water, DMF, DMA, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a11可藉由在使化合物a4與去保護劑反應之後，在存在鈀、配位體及鹼之情況下與化合物a10反應來獲得。 用於去保護反應之反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 去保護劑之實例包括鹽酸/乙酸乙酯、甲磺酸、三氟乙酸、硫酸、碘基三甲基矽烷、三氯化鋁、溴兒茶酚硼烷、氯化三甲基矽基、三氟甲磺酸三甲基矽基酯及其類似者。去保護劑之量可為化合物a4之1至100莫耳當量，較佳1至50莫耳當量。 鈀之實例包括乙酸鈀、Pd(PPh ₃) ₄、PdCl ₂(PPh ₃) ₂、Pd ₂(dba) ₃及其類似者。鈀之量可為化合物a4之0.01至5莫耳當量，較佳0.01至1莫耳當量。 配位體之實例包括2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯二苯、二環己基-[2-(2,4,6-三異丙基苯基)苯基]膦、(9,9-二甲基-9H-𠮿

-4,5-二基)雙(二苯基膦)及其類似者。配位體之量可為化合物a4之0.01至5莫耳當量，較佳0.01至1莫耳當量。 鹼之實例包括碳酸銫、碳酸鉀、碳酸鈉、三級丁醇鉀、三級丁醇鈉及其類似者。鹼之量可為化合物a4之1至10莫耳當量，較佳1至5莫耳當量。 反應溶劑之實例包括甲醇、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、四氫呋喃、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 反應溫度可為室溫至200℃，較佳為50℃至150℃，且反應視需要可在密封管中進行。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a11

wherein each symbol is as defined above. Compound a11 can be obtained by reacting compound a10 in the presence of palladium, a ligand and a base after reacting compound a4 with a deprotecting agent. Examples of reaction solvents used in the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and and the like, and these solvents may be used alone or in combination. Examples of deprotecting agents include hydrochloric acid/ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl chloride, Trimethylsilyl fluoromethanesulfonate and the like. The amount of the deprotecting agent can be 1 to 100 molar equivalents of compound a4, preferably 1 to 50 molar equivalents. Examples of palladium include palladium acetate, Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ and the like. The amount of palladium can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalent. Examples of ligands include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-tris Isopropylphenyl)phenyl]phosphine, (9,9-dimethyl-9H-𠮿

-4,5-diyl)bis(diphenylphosphine) and the like. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalent. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents to compound a4. Examples of the reaction solvent include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like , and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200°C, preferably from 50°C to 150°C, and the reaction can be carried out in a sealed tube if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a12可藉由使化合物a11與還原劑反應來獲得。 反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、乙酸、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 還原劑之實例包括硼氫化鈉與NiCl ₂(H ₂O) ₆、氫化鋁鋰、硼烷四氫呋喃、硼烷二甲基硫醚及其類似者。還原劑之量可為化合物a11之1至100莫耳當量，較佳1至10莫耳當量。 反應溫度可為0℃至200℃，較佳為0℃至100℃。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a12

wherein each symbol is as defined above. Compound a12 can be obtained by reacting compound a11 with a reducing agent. Examples of the reaction solvent include ethyl acetate, water, methylene chloride, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, and the like, And these solvents may be used alone or in combination. Examples of reducing agents include sodium borohydride and NiCl ₂ (H ₂ O) ₆ , lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide, and the like. The amount of the reducing agent can be 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents to compound a11. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a14可藉由在存在縮合劑及鹼之情況下使化合物a7與羧酸(化合物a13)反應來獲得。 反應溶劑之實例包括N,N-二甲基甲醯胺、乙醇、水、二氯甲烷、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 鹼之實例包括三乙胺、三級丁醇鉀、碳酸鉀、碳酸銫、二異丙基乙胺、DBU及其類似者。鹼之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 縮合劑之實例包括HATU、WSC、DCC、HOBt及其類似者。縮合劑之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 羧酸可以化合物a7之1至10莫耳當量，較佳1至5莫耳當量使用。 反應溫度可在冰冷卻至回流溫度，較佳室溫下。 反應時間可為0.1至24小時，較佳為1至5小時。 Preparation of compound a14

wherein each symbol is as defined above. Compound a14 can be obtained by reacting compound a7 with a carboxylic acid (compound a13) in the presence of a condensing agent and a base. Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and the Solvents such as these may be used alone or in combination. Examples of bases include triethylamine, potassium ter-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, and the like. The amount of the base can be 1 to 10 molar equivalents to compound a13, preferably 1 to 5 molar equivalents. Examples of condensing agents include HATU, WSC, DCC, HOBt, and the like. The amount of the condensing agent can be 1 to 10 molar equivalents of compound a13, preferably 1 to 5 molar equivalents. The carboxylic acid can be used in 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, to compound a7. The reaction temperature can be cooled with ice to reflux temperature, preferably at room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

其中各符號如上文所定義。 化合物a15可藉由在存在縮合劑及鹼之情況下使化合物a12與羧酸(化合物a13)反應來獲得。 反應溶劑之實例包括N,N-二甲基甲醯胺、乙醇、水、二氯甲烷、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 鹼之實例包括三乙胺、三級丁醇鉀、碳酸鉀、碳酸銫、二異丙基乙胺、DBU及其類似者。鹼之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 縮合劑之實例包括HATU、WSC、DCC、HOBt及其類似者。縮合劑之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 羧酸可以化合物a12之1至10莫耳當量，較佳1至5莫耳當量使用。 反應溫度可在冰冷卻至回流溫度，較佳室溫下。 反應時間可為0.1至24小時，較佳為1至5小時。 Preparation of compound a15

wherein each symbol is as defined above. Compound a15 can be obtained by reacting Compound a12 with a carboxylic acid (Compound a13) in the presence of a condensing agent and a base. Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and the Solvents such as these may be used alone or in combination. Examples of bases include triethylamine, potassium ter-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, and the like. The amount of the base can be 1 to 10 molar equivalents to compound a13, preferably 1 to 5 molar equivalents. Examples of condensing agents include HATU, WSC, DCC, HOBt, and the like. The amount of the condensing agent can be 1 to 10 molar equivalents of compound a13, preferably 1 to 5 molar equivalents. The carboxylic acid can be used in 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, to compound a12. The reaction temperature can be cooled with ice to reflux temperature, preferably at room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

其中各符號如上文所定義。 化合物a16可藉由使化合物a11與還原劑反應來獲得。 反應溶劑之實例包括乙酸乙酯、水、二氯甲烷、N,N-二甲基甲醯胺、乙醇、四氫呋喃、甲醇、乙酸、1,4-二㗁烷、乙腈、甲苯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 還原劑之實例包括氫氣與Pd碳、氫氣與Pd(OH) ₂及其類似者。還原劑之量可為化合物a11之1至100莫耳當量，較佳1至10莫耳當量。 反應溫度可為0℃至200℃，較佳為0℃至100℃。 反應時間可為0.1至24小時，較佳為1至12小時。 Preparation of compound a16

wherein each symbol is as defined above. Compound a16 can be obtained by reacting compound a11 with a reducing agent. Examples of the reaction solvent include ethyl acetate, water, methylene chloride, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, and the like, And these solvents may be used alone or in combination. Examples of reducing agents include hydrogen and Pd carbon, hydrogen and Pd(OH) ₂ , and the like. The amount of the reducing agent can be 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents to compound a11. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

其中各符號如上文所定義。 化合物a17可藉由在存在縮合劑及鹼之勤奮肯下使化合物a16與羧酸(化合物a13)反應來獲得。 反應溶劑之實例包括N,N-二甲基甲醯胺、乙醇、水、二氯甲烷、四氫呋喃、甲醇、1,4-二㗁烷、乙腈、甲苯、乙酸乙酯及其類似者，且此等溶劑可單獨使用或以組合形式使用。 鹼之實例包括三乙胺、三級丁醇鉀、碳酸鉀、碳酸銫、二異丙基乙胺、DBU及其類似者。鹼之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 縮合劑之實例包括HATU、WSC、DCC、HOBt及其類似者。縮合劑之量可為化合物a13之1至10莫耳當量，較佳1至5莫耳當量。 羧酸可以化合物a16之1至10莫耳當量，較佳1至5莫耳當量使用。 反應溫度可在冰冷卻至回流溫度，較佳室溫下。 反應時間可為0.1至24小時，較佳為1至5小時。 Preparation of compound a17

wherein each symbol is as defined above. Compound a17 can be obtained by reacting compound a16 with a carboxylic acid (compound a13) in the presence of a condensing agent and a base. Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and the Solvents such as these may be used alone or in combination. Examples of bases include triethylamine, potassium ter-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, and the like. The amount of the base can be 1 to 10 molar equivalents to compound a13, preferably 1 to 5 molar equivalents. Examples of condensing agents include HATU, WSC, DCC, HOBt, and the like. The amount of the condensing agent can be 1 to 10 molar equivalents of compound a13, preferably 1 to 5 molar equivalents. The carboxylic acid can be used in 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, to compound a16. The reaction temperature can be cooled with ice to reflux temperature, preferably at room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof is suitable for treating or preventing mycobacterial infection, especially non-tuberculous mycobacterial infection. Such compounds may act by interfering with ATP synthase in pathogenic mycobacteria, with inhibition of cytochrome bcl activity being the primary mode of action. The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof not only has the activity described above, but also has the utility as a medicine, and has any or all of the following excellent features: a) CYP enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like) have weak inhibitory activity. b) The compound exhibits good pharmacokinetics, such as high bioavailability, moderate clearance, high target tissue distribution and the like. c) The compound has high metabolic stability. d) The compound does not have an irreversible inhibitory effect on CYP enzymes (eg, CYP3A4) when the concentration is within the range described in this specification as the measurement conditions. e) The compound is not mutagenic. f) Compounds are associated with low cardiovascular risk. g) The compound has high solubility. h) Compounds cause less induction of drug metabolizing enzymes i) the compound presents a small risk of phototoxicity, j) the compound has a minor risk of hepatotoxicity, k) the compound has a small risk of nephrotoxicity, l) the compound has a small risk of gastrointestinal disorders, and m) The compound has a strong potency.

其中各符號具有與上文相同的含義 或其醫藥學上可接受之鹽，以及 (B)克拉黴素或其醫藥學上可接受之鹽，或阿奇黴素或其醫藥學上可接受之鹽。 術語「以組合為特徵之藥物」包括其中各化合物用作組合藥物之一實施例、其中各化合物用作套組之一實施例、其中各化合物同時投與之一實施例、其中各化合物依序投與之一實施例、其中各化合物間隔投與之一實施例及其中各化合物與其他藥物組合使用之一實施例。 提及投與，術語「同時」意謂例如以單次劑量或彈丸注射同時向個體投與化合物(A)及(B)。術語「依序」意謂在彼此之某一預定時間間隔內以某一預定順序向個體投與化合物(A)及(B)。舉例而言，投與順序(A)-(B)或(B)-(A)為可能的，其中各自之投與係在彼此之幾秒至幾小時內進行。術語「間隔」投與意謂在彼此之某一預定時間間隔內以某一預定順序向個體投與化合物(A)及(B)。舉例而言，投與順序(A)-(B)或(B)-(A)為可能的，其中各自之投與係在彼此之幾小時至一天內進行。 In an embodiment, the drug includes (A) a compound represented by formula (I):

Each symbol has the same meaning as above or a pharmaceutically acceptable salt thereof, and (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof. The term "a medicament characterized by combination" includes an embodiment in which the compounds are used as a combination drug, an embodiment in which the compounds are used as a kit, an embodiment in which the compounds are administered simultaneously, an embodiment in which the compounds are administered sequentially An embodiment of administration, an embodiment wherein each compound is administered at intervals, and an embodiment wherein each compound is used in combination with another drug. With reference to administration, the term "simultaneously" means that compounds (A) and (B) are administered to a subject at the same time, eg, in a single dose or bolus injection. The term "sequentially" means that compounds (A) and (B) are administered to a subject in a certain predetermined order within a certain predetermined time interval of each other. For example, a sequence of administrations (A)-(B) or (B)-(A) is possible, wherein the respective administrations are performed within seconds to hours of each other. The term "interval" administration means that compounds (A) and (B) are administered to a subject in some predetermined order within some predetermined time interval of each other. For example, a sequence of administrations (A)-(B) or (B)-(A) is possible, wherein the respective administrations are performed within hours to a day of each other.

The compound represented by formula (I) or its pharmaceutically acceptable salt can be used in combination with (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt, and its The antibacterial effect of (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof can be enhanced. In addition, (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof may be used in combination with the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, And it can enhance the antibacterial effect of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

其中各符號具有與上文相同的含義 或其醫藥學上可接受之鹽，以及 (B)克拉黴素或其醫藥學上可接受之鹽或阿奇黴素或其醫藥學上可接受之鹽及(C)氯法齊明或其醫藥學上可接受之鹽。 術語「以組合為特徵之藥物」包括其中各化合物用作組合藥物之一實施例、其中各化合物用作套組之一實施例、其中各化合物同時投與之一實施例、其中各化合物依序投與之一實施例、其中各化合物間隔投與之一實施例及其中各化合物與其他藥物組合使用之一實施例。 提及投與，術語「同時」意謂例如以單次劑量或彈丸注射同時向個體投與化合物(A)、(B)及(C)。術語「依序」意謂在彼此之某一預定時間間隔內以某一預定順序向個體投與化合物(A)、(B)及(C)。舉例而言，投與順序(A)-(B)-(C)、(B)-(C)-(A)、(C)-(A)-(B)、(B)-(A)-(C)、(A)-(C)-(B)或(C)-(B)-(A)為可能的，其中各自之投與係在彼此之幾秒至幾小時內進行。術語「間隔」投與意謂在彼此之某一預定時間間隔內以某一預定順序向個體投與化合物(A)、(B)及(C)。舉例而言，投與順序(A)-(B)-(C)、(B)-(C)-(A)、(C)-(A)-(B)、(B)-(A)-(C)、(A)-(C)-(B)或(C)-(B)-(A)為可能的，其中各自之投與係在彼此之幾小時至一天內進行。 In an embodiment, the drug includes (A) a compound represented by formula (I):

wherein each symbol has the same meaning as above or a pharmaceutically acceptable salt thereof, and (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and (C ) clofazimine or a pharmaceutically acceptable salt thereof. The term "a medicament characterized as a combination" includes an embodiment wherein each compound is used as a combination medicament, an embodiment wherein each compound is used as a kit, an embodiment wherein each compound is administered simultaneously, an embodiment wherein each compound is administered sequentially An embodiment of administration, an embodiment wherein each compound is administered at intervals, and an embodiment wherein each compound is used in combination with another drug. With reference to administration, the term "simultaneously" means that compounds (A), (B) and (C) are administered to a subject simultaneously, eg, in a single dose or bolus injection. The term "sequentially" means that compounds (A), (B) and (C) are administered to a subject in a certain predetermined order within a certain predetermined time interval of each other. For example, the order of administration (A)-(B)-(C), (B)-(C)-(A), (C)-(A)-(B), (B)-(A) - (C), (A)-(C)-(B) or (C)-(B)-(A) are possible, wherein the respective administrations are within seconds to hours of each other. The term "interval" administration means that compounds (A), (B) and (C) are administered to a subject in some predetermined order within some predetermined time interval of each other. For example, the order of administration (A)-(B)-(C), (B)-(C)-(A), (C)-(A)-(B), (B)-(A) - (C), (A)-(C)-(B) or (C)-(B)-(A) are possible, wherein the respective administrations are within a few hours to a day of each other.

The compound represented by formula (I) or its pharmaceutically acceptable salt can be combined with (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and (C) chlorine Fazimin or its pharmaceutically acceptable salt is used in combination, and it can enhance (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and/or (C ) antibacterial effect of clofazimine or a pharmaceutically acceptable salt thereof. In addition, (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine or its pharmaceutically acceptable salt can be combined with The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used in combination, and it can enhance the antibacterial effect of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

The route of administration of the drug of the present invention can be administered by oral or parenteral methods and is not particularly limited thereto.

In the case of oral administration, it can be used in the usual manner as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films), internal solutions (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcoholic solutions, aromatic solutions, extracts, decoctions, tinctures) and the like. The lozenge may be a dragee, film-coated, enteric-coated, extended release, dragee, sublingual, buccal, chewable, or orally disintegrating lozenge. Powders and granules may be dry syrups. Capsules may be soft capsules, microcapsules or sustained release capsules.

In the case of parenteral administration, any form of injections, drops, external preparations (for example, eye drops, nasal drops, ear drops, aerosols, inhalants, emulsions, Infusions, coatings, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories). Injections may be emulsions such as O/W, W/O, O/W/O or W/O/W types.

As the case may be, the effective amount of the compound used in the medicament of the present invention may be mixed with various pharmaceutical additives suitable for the dosage form of the pharmaceutical composition, such as excipients, binders, disintegrants and/or lubricant. In addition, the pharmaceutical composition can be used for children, elderly people, severe patients or surgery by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compounds used in the medicine of the present invention. Pediatric pharmaceutical compositions are preferably administered to patients under the age of 12 or 15 years. Pediatric pharmaceutical compositions can also be administered to patients less than 4 weeks old, 4 weeks old to less than 1 year old, 1 year old to less than 7 years old, 7 years old to less than 15 years old, or 15 years old to 18 years old. Pharmaceutical compositions for the elderly are preferably administered to patients over 65 years of age.

The dose of the drug of the present invention can be appropriately selected based on the clinically used dose. The mixing ratio of (A) the compound represented by formula (I) and (B) or (A) the compound represented by formula (I) Mixing ratios of the indicated compounds, (B) and (C). For example, when the subject to be administered is a human being, 0.01 to 400 parts by weight of (B) and/or (C) combination drug may be used per 1 part by weight of (A) compound represented by formula (I).

In general, pharmaceutical compositions contain an effective amount of the active compound to achieve its intended purpose. In one embodiment, a therapeutically effective amount means an amount effective to prevent or inhibit the development or progression of a disease characterized by mycobacterial infection or activity in the individual being treated. Determination of effective amounts is within the ability of those skilled in the art in view of the description provided herein.

In some embodiments, the medicaments of the invention are useful in the treatment and/or prevention of diseases and conditions characterized by mycobacterial activity or infection. Mycobacteria can be pathogenic or non-pathogenic. Mycobacteria can be Gram positive or Gram negative.

In some embodiments, the medicament of the present invention is suitable for treatment in humans (with either or both of immunocompetence and immunocompromise) and animals with tuberculosis, tuberculosis leprosy and non-tuberculous mycobacteria . Non-limiting examples of these include, but are not limited to, the following species and strains: Mycobacterium tuberculosis, such as Mycobacterium tuberculosis ( M. tuberculosis ), Mycobacterium bovis ( M. bovis ), Mycobacterium africanum ( M. africanum ), Mycobacterium murine ( M. microti ), Mycobacterium carinii ( M. canetti ); mycobacterium tuberculosis leprae, such as Mycobacterium leprae, Mycobacterium leprae ( M. Lepromatosis ); non Mycobacterium tuberculosis, eg M. abscessus , M. abcessus complex , M. avium, M. intracellulare, M. avium complex , Mycobacterium kansasii ( M. kansasii ), Mycobacterium mormoni ( M. malmoense ), Mycobacterium toads ( M. xenopi ), Mycobacterium mormoni , Mycobacterium flavences ( M. flavences ), scrofula M. scrofulaceum , M. chelonae , M. peregrinum , M. haemophilum , M. fortuitum , M. marinum , M. ulcerans , M. gordonae , haemophilus, M. mucogenicum , colorless Mycobacterium nonchromogenicum , M. terrae , M. terrae complex , M. asiaticum , M. celatum , Mycobacterium shimoidei ( M. shimoidei ), Mycobacterium simianum ( M. simiae ), Mycobacterium smegmatis ( M. smegmatis ), Mycobacterium szulgai ( M. szulgai ), Mycobacterium hidden M. conspicuum , M. genavense , M. immunogenum , M. xenopus.

In some embodiments, the medicaments of the invention are useful for the treatment in humans (both immunocompetent and immunocompromised) and animals with non-mycobacterial infectious diseases.

In some embodiments, the individual is known or suspected to be in need of treatment with a non-pathogenic mycobacterial strain Mycobacterium smegmatis, Mycobacterium vaccae ( M. vaccae ), Mycobacterium aureus ( M. aurum ), or Combination related one or more diseases.

In some embodiments, the individual is known or suspected to be in need of treatment for one or more diseases associated with Gram-positive bacteria, Staphylococcus aureus ( S. aureus ), Micrococcus luteus ( M. luteus ), or combinations thereof.

In some embodiments, the individual is known or suspected to be in need of treatment for one or more diseases associated with Gram-negative bacteria, Pseudomonas aeruginosa ( P. aeruginosa ), Acinetobacter baumannii ( A. baumanii ), or combinations thereof.

In some embodiments, the individual is known or suspected to be in need of treatment for one or more diseases associated with pathogenic mycobacterial strains Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii ( M . kansasaii ), H37Rv , Mycobacterium africanum, Mycobacterium carinii, Mycobacterium caprae ( M. caprae ), Mycobacterium muris, Mycobacterium manchee ( M. mungi ), Mycobacterium sealum ( M. pinnipedii ), Mycobacterium leprae, Mycobacterium avium, Myobacterium tuberculosis complex , tuberculosis or combinations thereof.

In some embodiments, the individual is known or suspected to be in need of treatment for one or more diseases associated with: non-pathogenic mycobacterial strains Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium aureus, Gram Positive bacteria, Staphylococcus aureus, Micrococcus luteus, Gram-negative bacteria, Pseudomonas aeruginosa, Acinetobacter baumannii, pathogenic mycobacterial strains Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv , Mycobacterium africanum, Mycobacterium carinii, Mycobacterium ovis, Mycobacterium muris, Mycobacterium manchee, Mycobacterium sealum, Mycobacterium avium, Mycobacterium tuberculosis, Tuberculosis or a combination thereof.

In some embodiments, there is provided a method comprising killing or inhibiting the population of one or more by contacting one or more members of the population with a compound or composition used in the invention It grows: Non-pathogenic mycobacterial strains Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium aureus, Gram-positive bacteria, Staphylococcus aureus, Micrococcus luteus, Gram-negative bacteria , Pseudomonas aeruginosa, Acinetobacter baumannii, pathogenic mycobacterial strains Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv , Mycobacterium africanum, Mycobacterium carinii, Mycobacterium sheep, Mycobacterium murine, Mycobacterium manzia, Mycobacterium sealum, Mycobacterium avium, Mycobacterium tuberculosis, tuberculosis, or combinations thereof. [example]

The invention is explained in more detail below by means of examples, but the invention is not limited to these examples.

The compound (A) represented by formula (I) used in the present invention can be prepared with reference to WO2011/057145, WO2017/049321, WO2011/113606, WO2021/050708, and the entire contents of each of these documents are hereby given as Incorporated by reference to the same extent as if set forth in detail.

In addition, the abbreviations used herein have the following meanings: Me: methyl Et: ethyl Bu: butyl Ph: phenyl PPh ₃ : triphenylphosphine Ac: acetyl EtOAc: ethyl acetate DMF: N,N- Dimethylformamide DMA: N,N-Dimethylacetamide TFA: Trifluoroacetic acid DMSO: Dimethylsulfoxide THF: Tetrahydrofuran WSC: 1-ethyl-3-(3-dimethylaminopropyl base) carbodiimide hydrochloride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium; 3-oxide Hexafluorophosphate DCC: N,N'-dicyclohexylcarbodiimide HOBt: Hydroxybenzotriazole Boc: Tertiary butoxycarbonyl t: Tertiary Cbz: Benzyloxycarbonyl dppf: 1,1' -Bis(diphenylphosphino)ferrocene Pd ₂ (dba) ₃ : ginseng(dibenzylideneacetone)dipalladium PdCl ₂ (dppf):[1,1'-bis(diphenylphosphino)ferrocene ] Palladium(II) chloride Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium(0) PdCl ₂ (PPh ₃ ) ₂ : bis(triphenylphosphine)palladium chloride

NMR analysis for each example was performed at 400 MHz using deuterated dimethylsulfoxide (d6-DMSO) or deuterated chloroform ( _CDCl3 ). Where NMR data are indicated, there are instances where not all peaks measured are described. "RT" in this specification means LC/MS: retention time of liquid chromatography/mass spectrometry, and the measurement conditions are as follows. (Method A) The UHPLC/MS data of the compounds were measured under the following conditions. Column: ACQUITY UPLC®BEH C18 (1.7 μm, id50×2.1 mm) (Waters) Flow rate: 0.8 mL/min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [ B] is an acetonitrile solution containing 0.1% formic acid. Gradient: A linear gradient from 5% to 100% solvent [B] for 3.5 minutes was performed with 100% solvent [B] held for 0.5 minutes. (Method B) The UHPLC/MS data of the compounds were measured under the following conditions. Column: ACQUITY UPLC®BEH C18 (1.7 μm, id50×2.1 mm) (Waters) Flow rate: 0.8 mL/min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, and [B] is acetonitrile. Gradient: A linear gradient from 5% to 100% solvent [B] for 3.5 minutes was performed with 100% solvent [B] held for 0.5 minutes. Hereinafter, MS (m/z) indicates a value observed in a mass spectrum. [instance 1]

步驟1 向化合物1 (1 g，7.19 mmol)於DMA (5 mL)中之溶液中添加K ₂CO ₃(1.49 g，10.78 mmol)及化合物2 (0.792 g，7.91 mmol)，且將溶液在100℃下攪拌4.5小時。在將反應溶液倒入水中之後，用乙酸乙酯萃取混合物。將有機層用水及鹽水洗滌，接著經硫酸鈉乾燥且過濾。在減壓下濃縮有機層之後，用己烷洗滌殘餘物以得到呈固體狀之化合物3 (1.01 g，產率：64%)。 1H-NMR (CDCl3) δ: 7.38-7.33 (1H, m), 7.27 (1H, dd, J = 12.9, 1.9 Hz), 6.91 (1H, t, J = 8.2 Hz), 3.50-3.41 (2H, m), 3.12-2.98 (3H, m), 2.88-2.77 (1H, m), 2.52-2.44 (1H, m), 1.12 (3H, d, J = 6.0 Hz)。 步驟2 向化合物3 (510 mg，2.33 mmol)於甲苯(5.0 mL)中之溶液中添加1-溴-4-(三氟甲基)苯4 (576 mg，2.56 mmol)、Pd(OAc) ₂(52.2 mg，0.233 mmol)、2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯二苯(217 mg，0.465 mmol)及三級丁醇鈉(447 mg，4.65 mmol)，將溶液在100℃下攪拌1小時。向反應溶液中添加水及乙酸乙酯。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮有機層，藉由矽膠層析(己烷/乙酸乙酯)純化殘餘物以得到呈黃色固體狀之化合物5 (543 mg，產率：64%)。 1H-NMR (CDCl3) δ: 7.39 (1H, dd, J = 8.4, 1.9 Hz), 7.30 (1H, dd, J = 12.5, 1.9 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.95 (1H, t, J = 9.2 Hz), 6.92 (2H, d, J = 8.3 Hz), 3.99-3.90 (1H, m), 3.55-3.50 (1H, m), 3.42-3.40 (1H, m), 3.35-3.26 (3H, m), 3.20-3.11 (1H, m), 1.16 (3H, d, J = 6.4 Hz) 步驟3 向化合物5 (546 mg，1.50 mmol)於MeOH (15 mL)中之溶液中添加5% Pd-C (320 g，0.150 mmol)及濃HCl (1.5 mL)，且將溶液在氫氣氛圍下在室溫下攪拌5小時。過濾反應混合物，在減壓下濃縮濾液。向反應混合物中添加NaOH水溶液及乙酸乙酯。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮有機層以得到呈黃色固體狀之化合物6 (440 mg，產率：80%)。 1H-NMR (CDCl3) δ: 7.16-7.10 (2H, m), 7.07-7.00 (2H, m), 6.98-6.88 (3H, m), 3.99-3.91 (1H, m), 3.86-3.80 (2H, m), 3.40-3.21 (4H, m), 3.17-3.10 (1H, m), 3.05-2.99 (1H, m), 1.19 (3H, d, J = 6.4 Hz)。 步驟4 向化合物6 (80 mg，0.209 mmol)於乙腈(2.0 mL)中之溶液中添加化合物7 (52 mg，0.230 mmol)、三乙胺(0.087 mL，0.626 mmol)、3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺(48.6 mg，0.313 mmol)及HOBt (28.2 mg，0.209 mmol)，將溶液在80℃下攪拌1小時。向反應溶液中添加水，且用乙酸乙酯萃取。將有機層用鹽水洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮有機層，藉由矽膠層析(CHCl ₃/甲醇)純化殘餘物以得到呈白色固體狀之化合物I-1-3 (55 mg，產率：45%)。 LC/MS方法A：m/z=590.2。[M+H]+，滯留時間：3.0 min [實例2] Preparation of compound I-1-3

Step 1 To a solution of Compound 1 (1 g, 7.19 mmol) in DMA (5 mL) was added K ₂ CO ₃ (1.49 g, 10.78 mmol) and Compound 2 (0.792 g, 7.91 mmol), and the solution was dissolved at 100 Stir at °C for 4.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and filtered. After the organic layer was concentrated under reduced pressure, the residue was washed with hexane to obtain Compound 3 (1.01 g, yield: 64%) as a solid. 1H-NMR (CDCl3) δ: 7.38-7.33 (1H, m), 7.27 (1H, dd, J = 12.9, 1.9 Hz), 6.91 (1H, t, J = 8.2 Hz), 3.50-3.41 (2H, m ), 3.12-2.98 (3H, m), 2.88-2.77 (1H, m), 2.52-2.44 (1H, m), 1.12 (3H, d, J = 6.0 Hz). Step 2 To a solution of compound 3 (510 mg, 2.33 mmol) in toluene (5.0 mL) was added 1-bromo-4-(trifluoromethyl)benzene 4 (576 mg, 2.56 mmol), Pd(OAc) ₂ (52.2 mg, 0.233 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (217 mg, 0.465 mmol) and sodium tertiary butoxide ( 447 mg, 4.65 mmol), the solution was stirred at 100°C for 1 hour. Water and ethyl acetate were added to the reaction solution. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to obtain Compound 5 (543 mg, yield: 64%) as a yellow solid. 1H-NMR (CDCl3) δ: 7.39 (1H, dd, J = 8.4, 1.9 Hz), 7.30 (1H, dd, J = 12.5, 1.9 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.95 ( 1H, t, J = 9.2 Hz), 6.92 (2H, d, J = 8.3 Hz), 3.99-3.90 (1H, m), 3.55-3.50 (1H, m), 3.42-3.40 (1H, m), 3.35 -3.26 (3H, m), 3.20-3.11 (1H, m), 1.16 (3H, d, J = 6.4 Hz) Step 3 To a solution of compound 5 (546 mg, 1.50 mmol) in MeOH (15 mL) 5% Pd—C (320 g, 0.150 mmol) and conc. HCl (1.5 mL) were added, and the solution was stirred at room temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Aqueous NaOH and ethyl acetate were added to the reaction mixture. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to obtain Compound 6 (440 mg, yield: 80%) as a yellow solid. 1H-NMR (CDCl3) δ: 7.16-7.10 (2H, m), 7.07-7.00 (2H, m), 6.98-6.88 (3H, m), 3.99-3.91 (1H, m), 3.86-3.80 (2H, m), 3.40-3.21 (4H, m), 3.17-3.10 (1H, m), 3.05-2.99 (1H, m), 1.19 (3H, d, J = 6.4 Hz). Step 4 To a solution of compound 6 (80 mg, 0.209 mmol) in acetonitrile (2.0 mL) was added compound 7 (52 mg, 0.230 mmol), triethylamine (0.087 mL, 0.626 mmol), 3-(((ethyl imino)methylene)amino)-N,N-dimethylpropan-1-amine (48.6 mg, 0.313 mmol) and HOBt (28.2 mg, 0.209 mmol), the solution was stirred at 80°C for 1 Hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (CHCl ₃ /methanol) to obtain Compound 1-1-3 (55 mg, yield: 45%) as a white solid. LC/MS method A: m/z = 590.2. [M+H]+, residence time: 3.0 min [Example 2]

向化合物7 (20 g，89 mmol)於乙腈(200 mL)中之溶液中添加N-甲基𠰌啉(19.6 mL，178 mmol)、3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(18.8 g，98 mmol)及HOBt (18.01 g，98 mmol)，將溶液在室溫下攪拌超過15小時。向反應溶液中添加水，且過濾反應混合物。將殘餘物用水洗滌且在減壓下乾燥以得到呈固體狀之化合物8 (19.4 g，產率：64%)。 1H-NMR (CDCl3) δ: 9.26 (1H, d, J = 1.3 Hz), 8.14 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 9.4 Hz), 7.62-7.44 (4H, m), 3.37 (2H, q, J = 7.5 Hz), 1.53 (3H, t, J = 7.5 Hz)。 [實例3] Preparation of Compound 8

To a solution of compound 7 (20 g, 89 mmol) in acetonitrile (200 mL) was added N-methyl phenoline (19.6 mL, 178 mmol), 3-(((ethylimino)methylene) Amino)-N,N-dimethylpropan-1-amine hydrochloride (18.8 g, 98 mmol) and HOBt (18.01 g, 98 mmol), the solution was stirred at room temperature over 15 hours. Water was added to the reaction solution, and the reaction mixture was filtered. The residue was washed with water and dried under reduced pressure to obtain Compound 8 (19.4 g, yield: 64%) as a solid. 1H-NMR (CDCl3) δ: 9.26 (1H, d, J = 1.3 Hz), 8.14 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 9.4 Hz), 7.62-7.44 (4H, m), 3.37 (2H, q, J = 7.5 Hz), 1.53 (3H, t, J = 7.5 Hz). [Example 3]

向化合物9 (4.9 g，23.7 mmol)於乙腈(99 mL)中之溶液中添加N-甲基𠰌啉(2.86 mL，26 mmol)、3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(4.04 g，26 mmol)及HOBt (3.2 g，23.7 mmol)，將溶液在室溫下攪拌超過22小時。向反應溶液中添加水，且過濾反應混合物。將殘餘物用水洗滌，且在減壓下乾燥以得到呈白色固體狀之化合物10 (5.09 g，產率：66%)。 1H-NMR (CDCl3) δ: 9.18 (1H, dd, J = 7.5, 5.4 Hz), 8.14 (1H, dt, J = 8.4, 0.9 Hz), 7.59 (1H, dd, J = 16.1, 8.0 Hz), 7.54-7.40 (3H, m), 6.98 (1H, td, J = 7.5, 2.7 Hz), 3.35 (2H, q, J = 7.5 Hz), 1.52 (3H, t, J = 7.5 Hz)。 [實例4] Preparation of compound 10

To a solution of compound 9 (4.9 g, 23.7 mmol) in acetonitrile (99 mL) was added N-methylmethanolinoline (2.86 mL, 26 mmol), 3-(((ethylimino)methylene) Amino)-N,N-dimethylpropan-1-amine hydrochloride (4.04 g, 26 mmol) and HOBt (3.2 g, 23.7 mmol), and the solution was stirred at room temperature over 22 hours. Water was added to the reaction solution, and the reaction mixture was filtered. The residue was washed with water, and dried under reduced pressure to give compound 10 (5.09 g, yield: 66%) as a white solid. 1H-NMR (CDCl3) δ: 9.18 (1H, dd, J = 7.5, 5.4 Hz), 8.14 (1H, dt, J = 8.4, 0.9 Hz), 7.59 (1H, dd, J = 16.1, 8.0 Hz), 7.54-7.40 (3H, m), 6.98 (1H, td, J = 7.5, 2.7 Hz), 3.35 (2H, q, J = 7.5 Hz), 1.52 (3H, t, J = 7.5 Hz). [Example 4]

向化合物6 (70 mg，0.183 mmol)於乙腈(1.0 mL)中之溶液中添加化合物9 (41.8 mg，0.201 mmol)、三乙胺(0.051 mL，0.365 mmol)、3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(52.5 mg，0.274 mmol)及HOBt (24.7 mg，0.183 mmol)，將溶液在50℃下攪拌1小時。向反應溶液中添加飽和NaHCO ₃水溶液，且用乙酸乙酯萃取。將有機層用水及鹽水洗滌，且經無水硫酸鎂乾燥。將有機層過濾且在減壓下濃縮，藉由矽膠層析(己烷/乙酸乙酯)純化殘餘物以得到呈白色固體狀之化合物I-1-38 (78 mg，產率：75%)。 1H-NMR (CDCl3) δ: 9.44 (1H, t, J = 5.6 Hz), 7.22 (1H, s), 7.14-7.07 (4H, m), 6.97-6.92 (3H, m), 6.80 (1H, t, J = 7.3 Hz), 6.06 (1H, s), 4.63 (2H, d, J = 3.8 Hz), 3.95 (1H, d, J = 2.0 Hz), 3.38-3.27 (4H, m), 3.17-3.14 (1H, m), 3.06-2.95 (3H, m), 1.44-1.40 (3H, m), 1.19 (3H, d, J = 4.5 Hz)。 LC/MS方法B：m/z=574.25 [M+H]+，滯留時間：2.99 min [實例5] Preparation of compound I-1-38

To a solution of compound 6 (70 mg, 0.183 mmol) in acetonitrile (1.0 mL) was added compound 9 (41.8 mg, 0.201 mmol), triethylamine (0.051 mL, 0.365 mmol), 3-(((ethylidene Amino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (52.5 mg, 0.274 mmol) and HOBt (24.7 mg, 0.183 mmol), the solution was stirred at 50°C 1 hour. To the reaction solution was added saturated aqueous NaHCO ₃ , and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give Compound 1-1-38 (78 mg, yield: 75%) as a white solid . 1H-NMR (CDCl3) δ: 9.44 (1H, t, J = 5.6 Hz), 7.22 (1H, s), 7.14-7.07 (4H, m), 6.97-6.92 (3H, m), 6.80 (1H, t , J = 7.3 Hz), 6.06 (1H, s), 4.63 (2H, d, J = 3.8 Hz), 3.95 (1H, d, J = 2.0 Hz), 3.38-3.27 (4H, m), 3.17-3.14 (1H, m), 3.06-2.95 (3H, m), 1.44-1.40 (3H, m), 1.19 (3H, d, J = 4.5 Hz). LC/MS method B: m/z=574.25 [M+H]+, retention time: 2.99 min [Example 5]

向化合物6 (1.5 g，3.91 mmol)於二氯甲烷(1.0 mL)中之溶液中添加化合物11 (1.32 g，4.3 mmol)及三乙胺(0.814 mL，5.87 mmol)，將溶液在室溫下攪拌15小時。藉由胺基矽膠及矽膠層析(CHCl ₃/甲醇)純化反應溶液以得到呈白色固體狀之化合物I-1-2 (1.76 g，產率：81%)。 LC/MS方法A：m/z=574.25 [M+H]+，滯留時間：2.99 min [實例6] Preparation of compound I-1-2

Compound 11 (1.32 g, 4.3 mmol) and triethylamine (0.814 mL, 5.87 mmol) were added to a solution of compound 6 (1.5 g, 3.91 mmol) in dichloromethane (1.0 mL), and the solution was brought to room temperature Stir for 15 hours. The reaction solution was purified by amine silica gel and silica gel chromatography (CHCl ₃ /methanol) to obtain compound I-1-2 (1.76 g, yield: 81%) as a white solid. LC/MS method A: m/z=574.25 [M+H]+, retention time: 2.99 min [Example 6]

向化合物6 (50 mg，0.130 mmol)於二氯甲烷(0.8 mL)中之溶液中添加化合物13 (29.8 g，0.156 mmol)、三乙胺(0.054 mL，0.391 mmol)、3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺(30.4 mg，0.196 mmol)及HOBt (8.8 mg，0.065 mmol)，將溶液在室溫下攪拌15小時。向反應溶液中添加飽和NaHCO3水溶液，且用二氯甲烷萃取。將有機層用水及鹽水洗滌，且經無水硫酸鎂乾燥。將有機層過濾且在減壓下濃縮。藉由矽膠層析(CHCl ₃/甲醇)純化殘餘物以得到呈白色固體狀之化合物I-1-25 (47 mg，產率：74.5%)。 LC/MS方法A：m/z=556.3 [M+H]+，滯留時間：2.73 min [實例7] Preparation of Compound I-1-25

To a solution of compound 6 (50 mg, 0.130 mmol) in dichloromethane (0.8 mL) was added compound 13 (29.8 g, 0.156 mmol), triethylamine (0.054 mL, 0.391 mmol), 3-(((ethyl imino)methylene)amino)-N,N-dimethylpropan-1-amine (30.4 mg, 0.196 mmol) and HOBt (8.8 mg, 0.065 mmol), and the solution was stirred at room temperature for 15 Hour. To the reaction solution was added saturated aqueous NaHCO 3 , and extracted with dichloromethane. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl ₃ /methanol) to give compound I-1-25 (47 mg, yield: 74.5%) as a white solid. LC/MS method A: m/z=556.3 [M+H]+, retention time: 2.73 min [Example 7]

步驟1 向化合物14 (5.05 g，21.7 mmol)於1,4-二㗁烷(76 mL)中之溶液中添加化合物15 (7.37 g，23.8 mmol)、PdCl ₂(PPh ₃) ₂(1.52 g，2.17 mmol)及2M Na ₂CO ₃水溶液(32.5 ml，65 mmol)。將反應混合物在100℃下攪拌1.5小時。在將反應溶液倒入水中之後，用乙酸乙酯萃取混合物。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮。藉由矽膠管柱層析(己烷-EtOAc)純化殘餘物以得到呈白色固體狀之化合物16 (6.59 g，19.7 mmol，91%)。 1H-NMR (400 MHz, CDCl3) δ: 7.78 (dd, 1H, J = 7.8, 1.3 Hz), 7.70 (dd, 1H, 11.6, 1.3 Hz), 6.04 (m, 1H), 4.15-4.05 (m, 2H), 3.92 (s, 3H), 3.62 (t, 2H, 5.4), 2.56-2.46 (m, 2H), 1.48 (s, 9H) 步驟2 向用惰性氛圍吹掃之化合物16 (6.49 g，19.4 mmol)於THF (100 ml)中之溶液中添加10% Pd(OH) ₂/C (5.44 g，1.94 mmol)。向反應混合物中裝入氫氣(1 atm)。將所得懸浮液劇烈攪拌6.5小時。將反應混合物用惰性氛圍吹掃，經由矽藻土墊過濾。用EtOAc洗滌濾餅，且在減壓下濃縮濾液以得到呈油狀物之粗材料。此粗材料不經進一步純化即用於下一反應。將粗材料溶解於THF (100 ml)中且在0℃下添加至LiAlH ₄(1.46 g，38.5 mmol)於THF (100ml)中之懸浮液中。在攪拌5 min之後，向反應混合物中添加十水合硫酸鈉(24.83 g，77 mmol)且將反應物攪拌3小時。經由矽藻土墊過濾反應混合物。用EtOAc洗滌濾餅，且在減壓下濃縮濾液以得到呈油狀物之粗產物。此粗材料不經進一步純化即用於下一反應中。在-78℃下向粗材料於二氯甲烷(100 ml)中之溶液中添加Et ₃N (7.93 ml，57.2 mmol)及甲磺醯氯(3.28 g，28.6 mmol)。向反應溶液中添加H ₂O，且將混合物用乙酸乙酯萃取兩次。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮以得到呈油狀物之粗材料。此粗材料不經進一步純化即用於下一反應中。向粗材料於DMF (60 ml)中之溶液中添加NaN ₃(2.47 g，37.9 mmol)且將混合物在80℃下攪拌1小時。向反應溶液中添加H ₂O，且用乙酸乙酯萃取混合物。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮以得到呈油狀物之粗材料。此粗產物不經進一步純化即用於下一反應。向粗產物於THF (50 ml)中之溶液中添加PPh ₃(5.55 g，21.2 mmol)及H ₂O (3.18 ml，176 mmol)且將混合物在回流下攪拌2小時。接著在減壓下濃縮混合物，藉由矽膠管柱層析(EtOAc-CHCl ₃-MeOH)純化殘餘物以得到呈白色固體狀之化合物17 (對於5個步驟，4.11 g，13.3 mmol，69%)。 1H-NMR (400 MHz, CDCl3) δ: 7.15 (t, 1H, J = 7.7 Hz), 7.04 (d, 1H, J = 7.9 Hz), 7.00 (d, 1H, J = 11.3 Hz), 4.24 (s, 2H), 3.84 (s, 2H), 2.98-2.89 (m, 1H), 2.84-2.70 (m, 2H), 1.83-1.75 (m, 2H), 1.68-1.55 (4H, m), 1.48 (s, 9H) LC/MS方法：A，LC-MS：m/z=253。[M+H]+，滯留時間：1.67min 步驟3 向化合物17 (1.84 g，5.97 mmol)於二氯甲烷(20 ml)中之溶液中添加化合物11 (2.02 g，6.56 mmol)及Et ₃N (1.24 ml，8.95 mmol)，且將反應物在室溫下攪拌1小時。接著在減壓下濃縮反應混合物，且藉由矽膠層析(CHCl ₃/MeOH)純化殘餘物以得到呈白色固體狀之化合物18 (2.83 g，5.89 mmol，99%)。 LC/MS方法：A，LC-MS：m/z=481。[M+H]+，滯留時間：2.17 min 步驟4 向化合物18 (2.44 g，5.08 mmol)於二氯甲烷(20 ml)中之溶液中添加TFA (3.91 ml，50.8 mmol)，且將反應物在室溫下攪拌1小時。接著在減壓下濃縮反應混合物，且藉由胺基矽膠層析(CHCl ₃/MeOH)純化殘餘物以得到呈灰白色非晶形之化合物19 (1.83 g，4.81 mmol，95%)。 LC/MS方法：A，LC-MS：m/z=381。[M+H]+，滯留時間：1.00 min 步驟5 向化合物19 (100 mg，0.263 mmol)於THF中之溶液中添加化合物4 (95 mg，0.394 mmol)、Pd ₂(dba) ₃(24.1 mg，0.0026 mmol)、2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯二苯(49.1 mg，0.105 mmol)及NaOtBu (0.789 mmol)，且接著將反應物在60℃下攪拌1小時。向反應溶液中添加H ₂O，且用乙酸乙酯萃取混合物。將有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮。藉由矽膠層析(己烷/EtOAc)純化殘餘物以得到化合物I-1-1 (81.7 mg，0.151 mmol，57.5%)。 1H-NMR (400 MHz, CDCl3) δ: 9.32 (d, 1H, J = 7.5 Hz), 7.33 (s, 1H), 7.28-7.22 (m, 1H), 7.15-7.04 (m, 4H), 6.94 (d, 2H, J = 7.9 Hz), 6.77 (d, 1H, J = 6.5 Hz), 6.06 (s, 1H), 4.67 (d, 2H, J = 5.3 Hz), 3.80-3.72 (m, 2H), 3.05- 2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.69 (s, 3H), 2.43 (s, 3H), 1.95-1.83 (m, 4H) LC/MS方法：A，LC-MS：m/z=541。[M+H]+，滯留時間：2.42 min Preparation of compound I-1-1

Step 1 To a solution of compound 14 (5.05 g, 21.7 mmol) in 1,4-dioxane (76 mL) was added compound 15 (7.37 g, 23.8 mmol), PdCl ₂ (PPh ₃ ) ₂ (1.52 g, 2.17 mmol) and 2M aqueous _{Na2CO3 (} 32.5 ml, 65 mmol). The reaction mixture was stirred at 100°C for 1.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane-EtOAc) to give compound 16 (6.59 g, 19.7 mmol, 91%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.78 (dd, 1H, J = 7.8, 1.3 Hz), 7.70 (dd, 1H, 11.6, 1.3 Hz), 6.04 (m, 1H), 4.15-4.05 (m, 2H), 3.92 (s, 3H), 3.62 (t, 2H, 5.4), 2.56-2.46 (m, 2H), 1.48 (s, 9H) Step 2 to compound 16 (6.49 g, 19.4 mmol) in THF (100 ml) was added 10% Pd(OH) ₂ /C (5.44 g, 1.94 mmol). Hydrogen gas (1 atm) was charged to the reaction mixture. The resulting suspension was vigorously stirred for 6.5 hours. The reaction mixture was purged with an inert atmosphere and filtered through a pad of celite. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure to afford crude material as an oil. This crude material was used in the next reaction without further purification. The crude material was dissolved in THF (100 ml) and added to a suspension of LiAlH4 ₍ 1.46 g, 38.5 mmol) in THF (100 ml) at 0 °C. After stirring for 5 min, sodium sulfate decahydrate (24.83 g, 77 mmol) was added to the reaction mixture and the reaction was stirred for 3 hours. The reaction mixture was filtered through a pad of celite. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure to give the crude product as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in dichloromethane (100 ml) was added _Et3N (7.93 ml, 57.2 mmol) and methanesulfonyl chloride (3.28 g, 28.6 mmol) at -78 °C. To the reaction solution was added H ₂ O, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in DMF (60 ml) was added NaN3 ₍ 2.47 g, 37.9 mmol) and the mixture was stirred at 80 °C for 1 h. To the reaction solution was added _H2O , and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material as an oil. This crude product was used in the next reaction without further purification. To a solution of the crude product in THF (50 ml) was added _PPh3 (5.55 g, 21.2 mmol) and _H2O (3.18 ml, 176 mmol) and the mixture was stirred at reflux for 2 hours. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc- _CHCl3 -MeOH) to give compound 17 (4.11 g, 13.3 mmol, 69% for 5 steps) as a white solid . 1H-NMR (400 MHz, CDCl3) δ: 7.15 (t, 1H, J = 7.7 Hz), 7.04 (d, 1H, J = 7.9 Hz), 7.00 (d, 1H, J = 11.3 Hz), 4.24 (s , 2H), 3.84 (s, 2H), 2.98-2.89 (m, 1H), 2.84-2.70 (m, 2H), 1.83-1.75 (m, 2H), 1.68-1.55 (4H, m), 1.48 (s , 9H) LC/MS method: A, LC-MS: m/z=253. [M+H]+, retention time: 1.67 min Step 3 To a solution of compound 17 (1.84 g, 5.97 mmol) in dichloromethane (20 ml) was added compound 11 (2.02 g, 6.56 mmol) and Et ₃ N (1.24 ml, 8.95 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (CHCl ₃ /MeOH) to give compound 18 (2.83 g, 5.89 mmol, 99%) as a white solid. LC/MS method: A, LC-MS: m/z=481. [M+H]+, residence time: 2.17 min Step 4 To a solution of compound 18 (2.44 g, 5.08 mmol) in dichloromethane (20 ml) was added TFA (3.91 ml, 50.8 mmol), and the reaction Stir at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by amide silica gel chromatography (CHCl ₃ /MeOH) to give compound 19 (1.83 g, 4.81 mmol, 95%) as off-white amorphous. LC/MS method: A, LC-MS: m/z=381. [M+H]+, retention time: 1.00 min Step 5 To a solution of compound 19 (100 mg, 0.263 mmol) in THF was added compound 4 (95 mg, 0.394 mmol), Pd ₂ (dba) ₃ (24.1 mg , 0.0026 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (49.1 mg, 0.105 mmol) and NaOtBu (0.789 mmol), and then The reaction was stirred at 60°C for 1 hour. To the reaction solution was added _H2O , and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EtOAc) to give compound I-1-1 (81.7 mg, 0.151 mmol, 57.5%). 1H-NMR (400 MHz, CDCl3) δ: 9.32 (d, 1H, J = 7.5 Hz), 7.33 (s, 1H), 7.28-7.22 (m, 1H), 7.15-7.04 (m, 4H), 6.94 ( d, 2H, J = 7.9 Hz), 6.77 (d, 1H, J = 6.5 Hz), 6.06 (s, 1H), 4.67 (d, 2H, J = 5.3 Hz), 3.80-3.72 (m, 2H), 3.05- 2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.69 (s, 3H), 2.43 (s, 3H), 1.95-1.83 (m, 4H) LC/MS method: A, LC-MS : m/z=541. [M+H]+, residence time: 2.42 min

The following compounds were obtained according to the general synthetic methods and examples. The chemical structures and physical properties (LC/MS data) of the compounds are described below.

[Table 1]

[Table 2]

[table 3]

[Table 4]

[table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

pharmacology example (test instance 1) Determination of the IC85 of the test compound against Mycobacterium avium preparation 1 μL of the test compound stock solution in DMSO (200×final concentration) was added to a sterile 96-well round bottom microtiter plate. Serial 4-fold dilutions (8 to 0.0000076 μΜ) were performed from columns 1 to 11 directly in the microtiter plate. Untreated control samples with and without inoculum were included in the column 12 in each tray. Samples of M. avium ATCC700898 were obtained from 7H9 (5% OADC) agar plates. This sample was first diluted with CAMHB medium to obtain an optical density at 600 nm wavelength of 0.1 and then diluted 1/20 to yield an inoculum of approximately 5 x 10 exp6 colony forming units per ml. Microtiter plates were filled with 200 μL of inoculum solution. Incubate the dish in a stainless steel bucket at 37°C to prevent evaporation. After 3 days of incubation, resazurin was added to all wells. One day later, fluorescence was measured on an EnVision microdisk reader with an excitation wavelength of 543 nm and an emission wavelength of 590 nm and IC85 values were calculated.

The results of Test Example 1 are shown below.

[Table 22]

(test instance 2) Metabolic Stability Test Using commercially available pooled human liver microsomes, the compound of the present invention was reacted for a constant time, and the residual rate was calculated by comparing the reacted sample with the unreacted sample, thereby evaluating the degree of metabolism in the liver. In the presence of 1 mmol/L NADPH in 0.2 mL buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L KCl, 10 mmol/L MgCl) containing 0.5 mg protein/ml human liver microsomes The reaction (oxidation reaction) was carried out at 37° C. for 0 minutes or 30 minutes in the case. After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. Quantify the compound of the present invention in the supernatant by LC/MS/MS or solid phase extraction (SPE)/MS, and calculate the remaining amount of the compound of the present invention after the reaction, so that the amount of the compound at the reaction time of 0 minutes is 100 %.

The results of Test Example 2 are shown below.

[Table 23]

I-1-3

I-1-149

I-1-144

I-2-6

I-1-25

I-1-42

I-1-29

I-1-39

I-1-43 Biological Examples - The compounds used in the combination regimen are as follows: ● Clarithromycin - "CAM" ● Azithromycin - "AZM" ● Rifamycin - "RFP" ● Ethambutol - "ETB" ● Clofazimine - "CFZ " ● The following "bc1 inhibitors":

I-1-3

I-1-149

I-1-144

I-2-6

I-1-25

I-1-42

I-1-29

I-1-39

I-1-43

Design of the Study (Test Example 3) There were 15 study groups with 4 mice per group [Table 24] research group Treatment (compound/dose, mg/kg) formulation concentration 1 CAM 200 mg/kg + CFZ load CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL 2 CAM 200 mg/kg + CFZ load + I-1-3 0.2 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + Il-3 0.02 mg/mL 3 CAM 200 mg/kg + CFZ load + I-1-3 1 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-3 0.1 mg/mL 4 CAM 200 mg/kg + CFZ load + I-1-3 5 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-3 0.5 mg/mL 5 CAM 200 mg/kg + CFZ load + I-1-149 0.2 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-149 0.02 mg/mL 6 CAM 200 mg/kg + CFZ load + I-1-149 1 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-149 0.1 mg/mL 7 CAM 200 mg/kg + CFZ load + I-1-149 5 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-149 0.5 mg/mL 8 CAM 200 mg/kg + CFZ load + I-1-144 0.2 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-144 0.02 mg/mL 9 CAM 200 mg/kg + CFZ load + 1-1-144 1 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-144 0.1 mg/mL 10 CAM 200 mg/kg + CFZ load + I-1-144 5 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-144 0.5 mg/mL 11 CAM 200 mg/kg + CFZ load + I-1-43 0.2 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-43 0.02 mg/mL 12 CAM 200 mg/kg + CFZ load + I-1-43 1 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-43 0.1 mg/mL 13 CAM 200 mg/kg + CFZ load + I-1-43 5 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-1-43 0.5 mg/mL 14 Control 1 (Day 1) 15 Control 2 (Day 8) In general, as can be seen from the table above, the relevant compound and formulation concentrations are given for the following doses: Clarithromycin (CAM) - administered in mice at a dose of 200 mg/kg, clinical dose in humans was 600 mg; formulation concentration was 20 mg/mL • Clofazimine (CFZ) Loading - On Day 1, a dose of 40 mg/kg was administered. After the second day, a dose of 6 mg/kg was administered. At the beginning of the second week, a dose of 15 mg/kg was administered, and after that day, a dose of 6 mg/kg was administered. This dosing mimics the AUC of repeated administration of 50 mg in humans.

Methods All treatments were evaluated against M. avium ATCC700898. All formulations were prepared in 0.5% (w/v) methylcellulose. All formulations were solutions and were prepared once a week. Timeline after infection of mice. Necropsy control 1 Start of treatment on day 1 Last treatment on day 1 Necropsy control on day 7 Necropsy treatment group on day 8 Mice were infected with M. avium strain on day 8. Clarithromycin-sensitive ATCC700898 was thawed at ambient temperature and diluted in saline for mouse inoculation. When inoculated with 0.07 mL of this dilution, each mouse received ¹⁰⁷ bacteria. Forty-eight female 8-week-old BALB/c mice Charles River were inoculated intranasally with 0.07 mL of bacterial suspension containing ±107 colony ^- forming units (CFU).

medication Dosing began on day 1. • The body weight of all mice was considered to be approximately 20 g. • All mice were orally dosed with 0.2 mL of the appropriate formulation, except for the untreated control group. • All groups were treated once daily on weekdays for one week (total of 5 doses/treatment). ● Give the last dose/treatment on Day 7.

autopsy On day 1 after infection, 4 control mice were sacrificed and lungs were collected in homogenization catheters. On day 8 after infection, 4 control mice and 40 treated mice were sacrificed and lungs were collected in homogenization catheters.

Assess infection and treat The effectiveness of the treatment was assessed by counting the number of colony forming units (CFU) in the lung. ● Add 1.8 mL of Mueller Hinton Broth (MHB) to each homogenization tube containing the lungs. • Lungs were homogenized and four 10-fold serial dilutions were prepared in MHB. ● From each individual lung, take 100 μL of the undiluted suspension and four serial 10-fold dilutions and spread it on a 7H10 agar plate. ● After 3 weeks of incubation at 35°C, count the CFU. ● The bactericidal effect of the treatment was defined as a significant reduction in the mean CFU in the treatment group relative to the pre-treatment value.

Preparation medium 7H10 agar + 5% OADC ● Dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water. ● Add 5 mL of glycerol ● Autoclave at 121°C for 10 min and cool to 55°C ● Add 50 mL Middlebrook OADC Enrichment (BD 212240) ● Keep at 55℃ ● Pipette 20 mL agar solution/plate ● Store at 4°C until coagulated before use

Results [Table 25] research group Treatment (compound/dose, mg/kg) Average Log 10 standard deviation 1 CAM 200 mg/kg + CFZ load 5.49 0.04 2 CAM 200 mg/kg + CFZ load + I-1-3 0.2 mg/kg 5.09 0.17 3 CAM 200 mg/kg + CFZ load + I-1-3 1 mg/kg 4.71 0.08 4 CAM 200 mg/kg + CFZ load + I-1-3 5 mg/kg 4.3 0.42 5 CAM 200 mg/kg + CFZ load + I-1-149 0.2 mg/kg 5.31 0.12 6 CAM 200 mg/kg + CFZ load + I-1-149 1 mg/kg 5.09 0.12 7 CAM 200 mg/kg + CFZ load + I-1-149 5 mg/kg 4.6 0.18 8 CAM 200 mg/kg + CFZ load + I-1-144 0.2 mg/kg 5.15 0.09 9 CAM 200 mg/kg + CFZ load + I-1-144 1 mg/kg 4.88 0.24 10 CAM 200 mg/kg + CFZ load + I-1-144 5 mg/kg 4.37 0.15 11 CAM 200 mg/kg + CFZ load + I-1-43 0.2 mg/kg 5.09 0.14 12 CAM 200 mg/kg + CFZ load + I-1-43 1 mg/kg 4.76 0.10 13 CAM 200 mg/kg + CFZ load + I-1-43 5 mg/kg 4.39 0.13 14 Control 1 (Day 1) 6.83 0.13 15 Control 2 (Day 8) 6.23 0.06 The above results can be seen with reference to Figure 1, which shows the respective mean log10 values of CFU for each of the 15 study groups. It also shows a "cut-off" value of 2.00, which is basically a value where the CFU (or bacterial infection) is too low for it to be accurately measured or the CFU is below detectable levels. ● Dual combination of clarithromycin + clofazimine Produced an effect resulting in a mean log10 reduction of 5.49 The triple combination of clarithromycin + clofazimine + I-1-3 demonstrated potent efficacy in a dose-dependent manner with I-1-3 Clarithromycin + chlorine The triple combination of Zimin + I-1-149 showed potent efficacy by I-1-149 in a dose-dependent manner The triple combination of clarithromycin + clofazimine + I-1-144 showed potent efficacy by I-1-149 144 exhibited potent efficacy in a dose-dependent manner Triple combination of clarithromycin + clofazimine + I-1-43 exhibited potent efficacy in a dose-dependent manner by I-1-43

(Test Example 4) There are 6 study groups and 4 mice per group [Table 26] research group Treatment (compound/dose, mg/kg) formulation concentration 1 CAM 200 mg/kg + CFZ load CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL 2 CAM 200 mg/kg + CFZ load + I-2-6 0.2 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-2-6 0.02 mg/mL 3 CAM 200 mg/kg + CFZ load + I-2-6 1 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-2-6 0.1 mg/mL 4 CAM 200 mg/kg + CFZ load + I-2-6 5 mg/kg CAM 20 mg/mL + CFZ 4 mg/mL or 0.6 mg/mL or 1.5 mg/mL + I-2-6 0.5 mg/mL 5 Control 1 (Day 1) 6 Control 2 (Day 8) The protocol is almost the same as that described in Test Example 3 above.

Results [Table 27] research group Treatment (compound/dose, mg/kg) Average Log10 standard deviation 1 CAM 200 mg/kg + CFZ load 5.69 0.09 2 CAM 200 mg/kg + CFZ load + I-2-6 0.2 mg/kg 5.43 0.07 3 CAM 200 mg/kg + CFZ load + I-2-6 1 mg/kg 5.14 0.13 4 CAM 200 mg/kg + CFZ load + I-2-6 5 mg/kg 4.41 0.16 5 Control 1 (Day 1) 6.8 0.17 6 Control 2 (Day 8) 6.27 0.08 The above results can be seen with reference to Figure 2, which shows the respective mean log10 values of CFU for each of the 6 study groups. It also exhibited a "cut-off" value of 2.00, which is basically a value at which the CFU (or bacterial infection) is too low for it to be accurately measured or the CFU is below detectable levels. As can be seen, compared to the control group: The dual combination of Clarithromycin + Clofazimine produced a mean log10 effect down to 5.69 The triple combination of Clarithromycin + Clofazimine + I-2-6 demonstrated potent potency by I-2-6 in a dose dependent manner effect

(Test Example 5) There were 15 study groups and 4 mice per group [Table 28] research group Treatment (compound/dose, mg/kg) formulation concentration 1 CAM 200 mg/kg + CFZ 20 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL 2 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 0.2 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-25 0.02 mg/mL 3 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 1 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-25 0.1 mg/mL 4 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 5 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-25 0.5 mg/mL 5 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 0.2 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-42 0.02 mg/mL 6 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 1 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-42 0.1 mg/mL 7 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 5 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-42 0.5 mg/mL 8 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-29 0.2 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-29 0.02 mg/mL 9 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-29 1 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-29 0.1 mg/mL 10 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-29 5 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-29 0.5 mg/mL 11 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 0.2 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-39 0.02 mg/mL 12 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 1 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-39 0.1 mg/mL 13 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 5 mg/kg CAM 20 mg/mL + CFZ 2 mg/mL + I-1-39 0.5 mg/mL 14 Control 1 (Day 1) 15 Control 2 (Day 8) The protocol is almost the same as that described in Test Example 3 above.

Results [Table 29] research group Treatment (compound/dose, mg/kg) Average Log10 standard deviation 1 CAM 200 mg/kg + CFZ 20 mg/kg 4.97 0.17 2 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 0.2 mg/kg 4.77 0.06 3 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 1 mg/kg 4.33 0.25 4 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-25 5 mg/kg 3.86 0.12 5 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 0.2 mg/kg 4.52 0.09 6 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 1 mg/kg 4.34 0.19 7 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-42 5 mg/kg 3.82 0.13 8 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-29 0.2 mg/kg 4.49 0.37 9 CAM 200 mg/kg + CFZ 20 mg/kg + Fl-29 1 mg/kg 4.30 0.24 10 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-29 5 mg/kg 3.84 0.16 11 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 0.2 mg/kg 4.86 0.10 12 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 1 mg/kg 4.64 0.13 13 CAM 200 mg/kg + CFZ 20 mg/kg + I-1-39 5 mg/kg 4.18 0.13 14 Control 1 (Day 1) 6.11 0.16 15 Control 2 (Day 8) 6.00 0.06 The above results can be seen with reference to Figure 3, which shows the respective mean log10 values of CFU for each of the 15 study groups. It also exhibited a "cut-off" value of 2.00, which is basically a value at which the CFU (or bacterial infection) is too low for it to be accurately measured or the CFU is below detectable levels. As can be seen, compared to the control group: The dual combination of Clarithromycin + Clofazimine produced a mean log10 effect down to 4.97 The triple combination of Clarithromycin + Clofazimine + I-1-25 demonstrated potent potency by I-1-25 in a dose dependent manner Efficacy ● The triple combination of clarithromycin + clofazimine + I-1-42 showed potent efficacy in a dose-dependent manner by I-1-42 ● The combination of clarithromycin + clofazimine + I-1-29 The triple combination showed potent efficacy by I-1-29 in a dose-dependent manner The triple combination of clarithromycin + clofazimine + I-1-39 demonstrated potent efficacy by I-1-39 in a dose-dependent manner

(Test Example 6) There are 6 study groups and 4 mice per group [Table 30] research group Treatment (compound/dose, mg/kg) formulation concentration 1 AZM 10 mg/kg 1 mg/mL 2 AZM 10 mg/kg + RFP 10 mg/kg + ETB 100 mg/kg 1 mg/mL + 1 mg/mL + 10 mg/mL 3 AZM 10 mg/kg + CFZ 20 mg/kg 1 mg/mL + 2 mg/mL 4 AZM 10 mg/kg + CFZ 20 mg/kg + I-1-3 1 mg/kg 1 mg/mL + 2 mg/mL + 0.1 mg/mL 5 Control 1 (Day 1) 6 Control 2 (Day 15) The protocol was almost identical to that described in Test Example 3 above, except for the bacterial load and treatment period. • Twenty-four female 8-week-old BALB/c mice Charles River were inoculated intranasally with 0.07 mL of bacterial suspension containing ±106 colony ^- forming units (CFU). • All groups were treated once daily on weekdays for 2 consecutive weeks (5 times/week for a total of 10 doses/treatment). • Give the last dose/treatment on Day 14.

Results [Table 31] research group Treatment (compound/dose, mg/kg) Average Log10 standard deviation 1 AZM 10 mg/kg 6.19 0.06 2 AZM 10 mg/kg + RFP 10 mg/kg + ETB 100 mg/kg 5.93 0.09 3 AZM 10 mg/kg + CFZ 20 mg/kg 5.47 0.11 4 AZM 10 mg/kg + CFZ 20 mg/kg + I-1-3 1 mg/kg 3.71 0.35 5 Control 1 (Day 1) 6.40 0.14 6 Control 2 (Day 15) 6.02 0.13 The above results can be seen with reference to Figure 4, which shows the respective mean log10 values of CFU for each of the 6 study groups. It also exhibited a "cut-off" value of 2.00, which is basically a value at which the CFU (or bacterial infection) is too low for it to be accurately measured or the CFU is below detectable levels. As can be seen, compared to the control group: Azithromycin+ The clinical standard therapy of rifamycin + ethambutol produced a mean log10 reduction from control 2 (mean log10 of 5.93) to 0.1 CFU The dual combination of azithromycin + clofazimine produced a mean log10 reduction of 5.47 Effects ● The triple combination of clarithromycin + clofazimine + I-1-3 showed a surprising reduction in CFU (mean log10 of 3.71)

I-1-3

I-1-144

I-1-149

I-2-6

I-1-29

I-1-39

I-1-25

I-1-42

I-1-43 Biological Examples - The compounds used in the combination regimen are as follows: • Clarithromycin - "CAM" • The following "bcl inhibitors":

I-1-3

I-1-144

I-1-149

I-2-6

I-1-29

I-1-39

I-1-25

I-1-42

I-1-43

Design of the Study (Test Example 7) There were 12 study groups. [Table 32] research group Treatment (compound/concentration, μg/ml) 1 CAM 1 μg/ml 2 I-1-3 1 μg/ml 3 I-1-144 1 μg/ml 4 I-1-149 1 μg/ml 5 I-1-6 1 μg/ml 6 I-1-29 1 μg/ml 7 I-1-39 1 μg/ml 8 I-1-25 1 μg/ml 9 I-1-42 1 μg/ml 10 I-1-43 1 μg/ml 11 Control (Day 0) 12 Control (Day 3)

Methods All treatments were evaluated with respect to M. avium ATCC700898. All compound solutions were prepared in 7H9 medium containing 5% OADC. Assay buffer also used 7H9 medium containing 5% OADC. Clarithromycin-sensitive ATCC700898 was cultured in 7H9 medium containing 5% OADC for 7 days at 37°C. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of stock solutions was performed by counting the number of colonies grown on 7H10 agar plates containing 5% OADC. Bactericidal studies were performed using media in 96-well plates (final volume 200 microliters/well). The stock solution was diluted by medium to a final concentration of approximately 1.0×10 ⁵ CFU/ml. All CAM and bcl inhibitors were dissolved in DMSO to make 1 mg/mL solutions. And then, the solution was diluted with culture medium to the final concentration as shown in Table 32. Assay plates were incubated at 37°C for 3 days.

Sampling point On day 0 after the start of the analysis, the determination of CFU was performed only in the control group for the calculation of the initial number of CFU. On day 3 after the start of the analysis, the determination of CFU was performed in all test groups.

Assess infection and treat Effectiveness of treatment was assessed by counting the number of colony forming units (CFU) in the lungs. ● The cultures of each group were serially diluted 10 times with normal saline. • From each individual group, 100 μL of these diluents were applied to 7H10 agar containing 5% OADC. ● After 2 weeks of incubation at 35°C, count the CFU. ● Define the bacteriostatic and bactericidal effect of the treatment as compared with the control CFU on day 0 and/or day 3. ● When the number of CFU in the largest diluent exceeds 3000 CFU, use 3000 CFU as the upper limit of detection.

Preparation medium 7H9 medium + 5% OADC ● Dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water ● Add 2.5 mL glycerol ● Autoclave at 121°C for 10 min and cool to about room temperature ● Add 25 mL Middlebrook OADC enrichment (BD 212240) ● Store at 4°C until ready to use 7H10 agar + 5% OADC ● Dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water. ● Add 5 mL of glycerol ● Autoclave at 121°C for 10 min and cool to 55°C ● Add 50 mL of Middlebrook OADC enrichment (BD 212240) ● Keep at 55℃ ● Pipette 20 mL agar solution/plate ● Store at 4°C until ready to use after coagulation

Results [Table 33] research group Treatment (compound/concentration, μg/ml) Log10 1 CAM 1 μg/ml 4.96 2 I-1-3 1 μg/ml 5.68 3 I-1-144 1 μg/ml 5.50 4 I-1-149 1 μg/ml 5.69 5 I-2-6 1 μg/ml 5.38 6 I-1-29 1 μg/ml 5.75 7 I-1-39 1 μg/ml 5.59 8 I-1-25 1 μg/ml 5.76 9 I-1-42 1 μg/ml 5.75 10 I-1-43 1 μg/ml 5.68 11 Control (Day 0) 5.23 12 Control (Day 3) >7.48 The above results can be seen with reference to Figure 5, which shows the respective log10 values of CFU for each of the 12 study groups. It also exhibited an "upper bound" value of 7.48, which is essentially a value at which the CFU is too high for it to be accurately measured. • All bc1 inhibitors showed bacteriostasis when log10 CFU ranged from 5.38 to 5.76.

(Test Example 8) There are 30 study groups. [Table 34] research group Treatment (compound/concentration, μg/ml) 1 CAM 1 μg/ml 2 CAM 1 μg/ml+ I-1-3 0.1 μg/ml 3 CAM 1 μg/ml + I-1-3 1 μg/ml 4 CAM 1 μg/ml + I-1-3 10 μg/ml 5 CAM 1 μg/ml + I-1-144 0.1 μg/ml 6 CAM 1 μg/ml + I-1-144 1 μg/ml 7 CAM 1 μg/ml + I-1-144 10 μg/ml 8 CAM 1 μg/ml + I-1-149 0.1 μg/ml 9 CAM 1 μg/ml + I-1-149 1 gg/ml 10 CAM 1 μg/ml + I-1-149 10 μg/ml 11 CAM 1 μg/ml + I-2-6 0.1 μg/ml 12 CAM 1 μg/ml + I-2-6 1 μg/ml 13 CAM 1 μg/ml + I-2-6 10 μg/ml 14 CAM 1 μg/ml + I-1-29 0.1 μg/ml 15 CAM 1 μg/ml + I-1-29 1 μg/ml 16 CAM 1 μg/ml + I-1-29 10 μg/ml 17 CAM 1 μg/ml + I-1-39 0.1 μg/ml 18 CAM 1 μg/ml + I-1-39 1 μg/ml 19 CAM 1 μg/ml + I-1-39 10 μg/ml 20 CAM 1 μg/ml + I-1-25 1 μg/ml twenty one CAM 1 μg/ml + I-1-25 1 μg/ml twenty two CAM 1 μg/ml + I-1-25 10 μg/ml twenty three CAM 1 μg/ml + I-1-42 0.1 μg/ml twenty four CAM 1 μg/ml + I-1-42 1 μg/ml 25 CAM 1 μg/ml + I-1-42 10 μg/ml 26 CAM 1 μg/ml + I-1-43 0.1 μg/ml 27 CAM 1 μg/ml + I-1-43 1 μg/ml 28 CAM 1 μg/ml + I-1-43 10 μg/ml 29 Control (Day 0) 30 Control (Day 3) The protocol is almost the same as that described in Test Example 7 above.

Results [Table 35] research group Treatment (compound/concentration, μg/ml) Log 10 1 CAM 1 μg/ml 4.69 2 CAM 1 μg/ml + I-1-3 0.1 μg/ml 4.67 3 CAM 1 μg/ml + I-1-3 1 μg/ml 4.60 4 CAM 1 μg/ml + I-1-3 10 μg/ml 4.08 5 CAM 1 μg/ml + I-1-144 0.1 μg/ml 4.43 6 CAM 1 μg/ml + I-1-144 1 μg/ml 4.04 7 CAM 1 μg/ml + I-1-144 10 μg/ml 3.90 8 CAM 1 μg/ml + I-1-149 0.1 μg/ml 4.71 9 CAM 1 μg/ml + I-1-149 1 μg/ml 4.45 10 CAM 1 μg/ml + I-1-149 10 μg/ml 4.15 11 CAM 1 μg/ml + I-2-6 0.1 μg/ml 4.88 12 CAM 1 μg/ml + I-2-6 1 μg/ml 4.54 13 CAM 1 μg/ml + I-2-6 10 μg/ml 4.26 14 CAM 1 μg/ml + I-1-29 0.1 μg/ml 4.88 15 CAM 1 μg/ml + I-1-29 1 μg/ml 4.79 16 CAM 1 μg/ml + I-1-29 10 μg/ml 4.15 17 CAM 1 μg/ml + I-1-39 0.1 μg/ml 4.80 18 CAM 1 μg/ml + I-1-39 1 μg/ml 4.82 19 CAM 1 μg/ml + I-1-39 10 μg/ml 4.20 20 CAM 1 μg/ml + I-1-39 10 μg/ml 4.81 twenty one CAM 1 μg/ml + I-1-25 1 μg/ml 4.85 twenty two CAM 1 μg/ml + I-1-25 10 μg/ml 4.20 twenty three CAM 1 μg/ml + I-1-42 0.1 μg/ml 4.88 twenty four CAM 1 μg/ml + I-1-42 1 μg/ml 4.74 25 CAM 1 μg/ml + I-1-42 10 μg/ml 4.20 26 CAM 1 μg/ml + I-1-43 0.1 μg/ml 4.77 27 CAM 1 μg/ml + I-1-43 1 μg/ml 4.71 28 CAM 1 μg/ml + I-1-43 10 μg/ml 3.95 29 Control (Day 0) 5.01 30 Control (Day 3) 7.95 The above results can be seen with reference to Figure 6, which shows the respective log10 values of CFU for each of the 30 study groups. It also exhibits an "upper limit" value of 8.48, which is essentially a value at which the CFU is too high for it to be accurately measured. As can be seen, compared to the control group: Clarithromycin 1 µg/ml + bc1 inhibitor 10 µg/ml The dual combination produced a log10 effect down to 3.90 to 4.26. ● The dual combination of clarithromycin 1 µg/ml + several bc1 inhibitors (I-1-144, I-1-149 and I-2-6) showed Concentration dependence.

(Test Example 9) There were 11 study groups and 4 mice per group [Table 36] research group Treatment (compound/concentration, μg/ml) 1 CAM 1 μg/ml 2 CAM 1 μg/ml + I-1-3 1 μg/ml 3 CAM 1 μg/ml + I-1-3 10 μg/ml 4 CAM 1 μg/ml + I-1-144 1 μg/ml 5 CAM 1 μg/ml + I-1-144 10 μg/ml 6 CAM 1 μg/ml + I-1-149 1 μg/ml 7 CAM 1 μg/ml + I-1-149 10 μg/ml 8 CAM 1 μg/ml + I-2-6 1 μg/ml 9 CAM 1 μg/ml + I-2-6 10 μg/ml 10 Control (Day 0) 11 Control (Day 3) Methods All treatments were evaluated with respect to M. avium ATCC700897. Clarithromycin-resistant ATCC700897 was cultured in 7H9 medium containing 5% OADC for 7 days at 37°C. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of stock solutions was performed by counting the number of colonies grown on 7H10 agar plates containing 5% OADC. Except for the strains used, the protocol was almost the same as that described in Test Example 7 above.

Results [Table 37] research group Treatment (compound/concentration, μg/ml) Log 10 1 CAM 1 μg/ml >6.48 2 CAM 1 μg/ml + I-1-3 1 μg/ml 4.95 3 CAM 1 μg/ml + I-1-3 10 μg/ml 4.80 4 CAM 1 μg/ml + I-1-144 1 μg/ml 4.98 5 CAM 1 μg/ml + I-1-144 10 μg/ml 4.71 6 CAM 1 μg/ml + I-1-149 1 μg/ml 4.92 7 CAM 1 μg/ml + I-1-149 10 μg/ml 4.82 8 CAM 1 μg/ml + I-2-6 1 μg/ml 4.97 9 CAM 1 μg/ml + I-2-6 10 μg/ml 4.75 10 Control (Day 0) 4.47 11 Control (Day 3) >6.48 The above results can be seen with reference to Figure 7, which shows the respective log10 values of CFU for each of the 11 study groups. It also exhibited an "upper bound" value of 6.48, which is essentially a value at which the CFU is too high for it to be accurately measured. It can be seen that, compared to the control group: • Despite no bacteriostatic effect in the case of clarithromycin alone, The dual combination of clarithromycin + bcl inhibitor showed bacteriostatic effect when log10 CFU was 4.71 to 4.98.

(Test Example 10) There are 26 study groups. [Table 38] research group Treatment (compound/concentration, μg/ml) 1 I-1-3 0.3 μg/ml 2 I-1-3 1 μg/ml 3 I-1-3 3 μg/ml 4 I-1-3 10 μg/ml 5 CAM 1 μg/ml 6 CAM 1 μg/ml + I-1-3 0.3 μg/ml 7 CAM 1 μg/ml + I-1-3 1 μg/ml 8 CAM 1 μg/ml + I-1-3 3 μg/ml 9 CAM 1 μg/ml + I-1-3 10 μg/ml 10 CAM 3 μg/ml 11 CAM 3 μg/ml + I-1-3 0.3 μg/ml 12 CAM 3 μg/ml + I-1-3 1 μg/ml 13 CAM 3 μg/ml + I-1-3 3 μg/ml 14 CAM 3 μg/ml + I-1-3 10 μg/ml 15 CAM 10 μg/ml 16 CAM 10 μg/ml + I-1-3 0.3 μg/ml 17 CAM 10 μg/ml + I-1-3 1 μg/ml 18 CAM 10 μg/ml + I-1-3 3 μg/ml 19 CAM 10 μg/ml + I-1-3 10 μg/ml 20 CAM 30 μg/ml twenty one CAM 30 μg/ml + I-1-3 0.3 μg/ml twenty two CAM 30 μg/ml + I-1-3 1 μg/ml twenty three CAM 30 μg/ml + I-1-3 3 μg/ml twenty four CAM 30 μg/ml + I-1-3 10 μg/ml 25 Control (Day 0) 26 Control (Day 3) The protocol is almost the same as that described in Test Example 9 above.

Results [Table 39] research group Treatment (compound/concentration, μg/ml) Log 10 1 I-1-3 0.3 μg/ml >6.48 2 I-1-3 1 μg/ml 6.05 3 I-1-3 3 μg/ml 5.77 4 I-1-3 10 μg/ml 5.78 5 CAM 1 μg/ml >6.48 6 CAM 1 μg/ml + I-1-3 0.3 μg/ml >6.48 7 CAM 1 μg/ml + I-1-3 1 μg/ml 5.98 8 CAM 1 μg/ml + I-1-3 3 μg/ml 5.54 9 CAM 1 μg/ml + I-1-3 10 μg/ml 5.58 10 CAM 3 μg/ml >6.48 11 CAM 3 μg/ml + I-1-3 0.3 μg/ml 6.32 12 CAM 3 μg/ml + I-1-3 1 μg/ml 5.97 13 CAM 3 μg/ml + I-1-3 3 μg/ml 5.56 14 CAM 3 μg/ml + I-1-3 10 μg/ml 5.54 15 CAM 10 μg/ml >6.48 16 CAM 10 μg/ml + I-1-3 0.3 μg/ml 6.16 17 CAM 10 μg/ml + I-1-3 1 μg/ml 5.86 18 CAM 10 μg/ml + I-1-3 3 μg/ml 5.51 19 CAM 10 μg/ml + I-1-3 10 μg/ml 5.49 20 CAM 30 μg/ml >6.48 twenty one CAM 30 μg/ml + I-1-3 0.3 μg/ml 6.13 twenty two CAM 30 μg/ml + I-1-3 1 μg/ml 5.86 twenty three CAM 30 μg/ml + I-1-3 3 μg/ml 5.59 twenty four CAM 30 μg/ml + I-1-3 10 μg/ml 5.58 25 Control (Day 0) 5.45 26 Control (Day 3) >6.48 The above results can be seen with reference to Figure 8, which shows the respective log10 values of CFU for each of the 26 study groups. It also exhibits an "upper limit" value of 6.48, which is essentially a value at which the CFU is too high for it to be accurately measured. As can be seen, compared to the control group: Regardless of the concentration of clarithromycin, and even in the absence of clarithromycin When the log10 CFU is 5.49 to 5.78, I-1-3 also shows obvious antibacterial effect at a concentration of 3 µg/ml or greater. ● When the log10 CFU is 5.86 to 6.05, the concentration is 1 µg/ml of I-1-3 also showed antibacterial effect.

I-1-3 Biological Examples - The compounds used in the combination regimen are as follows: • Clarithromycin - "CAM" • Clofazimine - CFZ • The following "bc1 inhibitors":

I-1-3

Design of the Study (Test Example 11) There were 6 study groups. [Table 40] research group Treatment (compound/concentration, μg/ml) 1 CAM 1 μg/ml 2 I-1-3 1 μg/ml 3 CAM 1 μg/ml + CFZ 1 μg/ml 4 CAM 1 μg/ml + CFZ 1 μg/ml+I-1-3 1 μg/ml 5 Control (Day 0) 6 Control (Day 1)

Methods All treatments were evaluated with respect to M. intracellulare ATCC 13950. All compound solutions were prepared in 7H9 medium containing 5% OADC. Assay buffer also used 7H9 medium containing 5% OADC. Clarithromycin-sensitive ATCC13950 was cultured in 7H9 medium containing 5% OADC for 7 days at 37°C. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of stock solutions was performed by counting the number of colonies grown on 7H10 agar plates containing 5% OADC. Bactericidal studies were performed using media in 96-well plates (final volume 200 microliters/well). The stock solution was diluted by medium to a final concentration of approximately 2.0×10 ⁵ CFU/ml. All CAM, CFZ and bcl inhibitors were dissolved in DMSO to make 1 mg/mL solutions. And then, the solution was diluted with culture medium to the final concentration as shown in Table 40. Assay plates were incubated at 37°C for 1 day.

Sampling point On day 0 after the start of the analysis, the determination of CFU was performed only in the control group for the calculation of the initial number of CFU. On day 1 after the start of the analysis, the determination of CFU was performed in all test groups.

Assess infection and treat Effectiveness of treatment was assessed by counting the number of colony forming units (CFU) in the lungs. ● The cultures of each group were serially diluted 10 times with normal saline. • From each individual group, 100 μL of these diluents were applied to 7H10 agar containing 5% OADC. ● After 2 weeks of incubation at 35°C, count the CFU. ● Define the bacteriostatic and bactericidal effect of the treatment as compared with the control CFU on day 0 and/or day 1. ● When the number of CFU in the largest diluent exceeds 500 CFU, use 500 CFU as the upper limit of detection.

Preparation medium 7H9 medium + 5% OADC ● Dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water ● Add 2.5 mL glycerol ● Autoclave at 121°C for 10 min and cool to about room temperature ● Add 25 mL Middlebrook OADC enrichment (BD 212240) ● Store at 4°C until ready to use 7H10 agar + 5% OADC ● Dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water. ● Add 5 mL of glycerol ● Autoclave at 121°C for 10 min and cool to 55°C ● Add 50 mL of Middlebrook OADC enrichment (BD 212240) ● Keep at 55℃ ● Pipette 20 mL agar solution/plate ● Store at 4°C until ready to use after coagulation

Results [Table 41] research group Treatment (compound/concentration, μg/ml) Log 10 1 CAM 1 (μg/ml 5.61 2 I-1-3 1 μg/ml >5.70 3 CAM 1 μg/ml + CFZ 1 μg/ml 5.61 4 CAM 1 μg/ml + CFZ 1 μg/ml+I-1-3 1 μg/ml 4.54 5 Control (Day 0) 5.64 6 Control (Day 1) >5.70 The above results can be seen with reference to Figure 9, which shows the respective log10 values of CFU for each of the 6 study groups. It also exhibited an "upper limit" value of 5.70, which is essentially a value at which the CFU is too high for it to be accurately measured. • Only group 4 clearly showed bactericidal effect when the log10 CFU was 4.54 on day 1.

(Test Example 12) There are 6 study groups and 4 mice per group [Table 42] research group Treatment (compound/dose, mg/kg) formulation concentration 1 CAM 200 mg/kg + RFP 10 mg/kg + ETB 100 mg/kg CAM 20 mg/mL + RFP 1 mg/mL + ETB 10 mg/mL 2 CAM 200 mg/kg + CFZ load CAM 20 mg/mL+ CFZ 6 mg/mL or 2 mg/mL or 0.9 mg/mL 3 CAM 200 mg/kg + CFZ load + I-1-3 1 mg/kg CAM 20 mg/mL + CFZ 6 mg/mL or 2 mg/mL or 0.9 mg/mL + I-1-3 0.1 mg/mL 4 CAM 200 mg/kg + CFZ load + I-1-3 5 mg/kg CAM 20 mg/mL + CFZ 6 mg/mL or 2 mg/mL or 0.9 mg/mL + I-1-3 0.5 mg/mL 5 Control 1 (Day 22) 6 Control 2 (Day 46) In general, as can be seen from the table above, the following doses are given for the relevant compound and formulation concentrations: • CFZ Loading - On the first day, a dose of 60 mg/kg was administered. After the second day, a dose of 9 mg/kg was administered. At the beginning of the second week, a dose of 20 mg/kg was administered, and after that day, a dose of 9 mg/kg was administered. This dosing mimics repeated administration of 50 mg of Cmax in humans.

Methods All treatments were evaluated with respect to M. avium ATCC13950. All formulations were prepared in 20% Tween20 80% in water (20% 2-hydroxypropyl-β-cyclodextrin and 0.6% hydroxypropylmethylcellulose, pH 3). All formulations were solutions and were prepared once a week. Timeline after infection of mice. Necropsy control 1 Start of treatment on day 22 Last treatment on day 22 Day 45 Necropsy control 2 Necropsy treatment group on day 46 Mice were infected with M. intracellulare strain on day 46. Clarithromycin-sensitive ATCC13950 was thawed at ambient temperature and diluted in saline for mouse inoculation. When inoculated with 0.07 mL of this dilution, each mouse received ¹⁰⁷ bacteria. Forty-eight female 8-week-old BALB/c mice Charles River were inoculated intranasally with 0.07 mL of bacterial suspension containing ±107 colony ^- forming units (CFU).

medication Dosing was started on day 22. • The body weight of all mice was considered to be approximately 20 g. • All mice were orally dosed with 0.2 mL of the appropriate formulation, except for the untreated control group. • All groups were treated once daily on weekdays for one week (total of 5 doses/treatment). ● Give the last dose/treatment on Day 45

autopsy On day 22 after infection, 4 control mice were sacrificed and lungs were collected in homogenization catheters. On day 46 after infection, 4 control mice and 40 treated mice were sacrificed and lungs were collected in homogenization catheters.

Assess infection and treat Effectiveness of treatment was assessed by counting the number of colony forming units (CFU) in the lungs. ● Add 1.8 mL of Mueller Hinton Broth (MHB) to each homogenization tube containing the lungs. • Lungs were homogenized and four 10-fold serial dilutions were made in MHB. ● From each individual lung, spread 100 μL of the undiluted suspension and four serial 10-fold dilutions on 7H10 agar plates. ● After 3 weeks of incubation at 35°C, count the CFU. • The bactericidal effect of the treatment was defined as a significant reduction in the mean number of CFU in the treatment group compared to the pre-treatment value.

Preparation medium 7H10 agar + 5% OADC ● Dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water. ● Add 5 mL of glycerol ● Autoclave at 121°C for 10 min and cool to 55°C ● Add 50 mL of Middlebrook OADC enrichment (BD 212240) ● Keep at 55℃ ● Pipette 20 mL agar solution/plate ● Store at 4°C until ready to use after coagulation

Results [Table 43] research group Treatment (compound/dose, mg/kg) Average Log 10 standard deviation 1 CAM 200 mg/kg + RFP 10 mg/kg + ETB 100 mg/kg 5.23 0.12 2 CAM 200 mg/kg + CFZ load 4.96 0.04 3 CAM 200 mg/kg + CFZ load + 11-3 1 mg/kg 2.05 0.10 4 CAM 200 mg/kg + CFZ load + 11-3 5 mg/kg <2.00 - 5 Control 1 (Day 22) 6.49 0.06 6 Control 2 (Day 46) 5.85 0.03 The above results can be seen with reference to Figure 10, which shows the respective mean log10 values of CFU for each of the 6 study groups. It also exhibited a "cut-off" value of 2.00, which is basically a value at which the CFU (or bacterial infection) is too low for it to be accurately measured or the CFU is below detectable levels. As can be seen, compared to the control group: The triple combination of clindamycin + rifamycin + ethambutol produced a mean log10 effect down to 5.23. The dual combination of clarithromycin + clofazimine showed an effect down to a mean log10 of 4.96 Clarithromycin The triple combination of +clofazimine+I-1-3 showed a surprising reduction in CFU (mean log10 of 2.05 in study arm 3 and below cutoff in study arm 4)

I-1-3 Biological Examples - The compounds used in the combination regimen are as follows: • Clarithromycin - "CAM" • Clofazimine - CFZ • The following "bc1 inhibitors":

I-1-3

Design of the Study (Test Example 13) There were 7 study groups. [Table 44] research group Treatment (compound/concentration, μg/ml) 1 CAM 1 μg/ml 2 CFZ 1 μg/ml 3 I-1-3 1 μg/ml 4 CAM 1 μg/ml + CFZ 1 μg/ml 5 CAM 1 μg/ml + CFZ 1 μg/ml+I-1-3 1 μg/ml 6 Control (Day 0) 7 Control (Day 2)

Methods All treatments were evaluated with respect to M. avium ATCC700897. All compound solutions were prepared in 7H9 medium containing 5% OADC. Assay buffer also used 7H9 medium containing 5% OADC. Clarithromycin-resistant ATCC700897 was cultured in 7H9 medium containing 5% OADC for 7 days at 37°C. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of stock solutions was performed by counting the number of colonies grown on 7H10 agar plates containing 5% OADC. Bactericidal studies were performed using media in 96-well plates (final volume 200 microliters/well). The stock solution was diluted by medium to a final concentration of approximately 2.0×10 ⁵ CFU/ml. All CAM, CFZ and bcl inhibitors were dissolved in DMSO to make 1 mg/mL solutions. And then, the solution was diluted with culture medium to the final concentration as shown in Table 44. Assay plates were incubated at 37°C for 2 days.

Sampling point On day 0 after the start of the analysis, the determination of CFU was performed only in the control group for the calculation of the initial number of CFU. The determination of CFU was performed in all test groups on day 2 after the start of the analysis.

Assess infection and treat Effectiveness of treatment was assessed by counting the number of colony forming units (CFU) in the lungs. ● The cultures of each group were serially diluted 10 times with normal saline. • From each individual group, 100 μL of these diluents were applied to 7H10 agar containing 5% OADC. ● After 2 weeks of incubation at 35°C, count the CFU. ● Define the bacteriostatic and bactericidal effect of the treatment as compared with the control CFU on day 0 and/or day 2. ● When the number of CFU in the largest diluent exceeds 500 CFU, use 500 CFU as the upper limit of detection.

Preparation medium 7H9 medium + 5% OADC ● Dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water ● Add 2.5 mL glycerol ● Autoclave at 121°C for 10 min and cool to about room temperature ● Add 25 mL Middlebrook OADC enrichment (BD 212240) ● Store at 4°C until ready to use 7H10 agar + 5% OADC ● Dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water. ● Add 5 mL of glycerol ● Autoclave at 121°C for 10 min and cool to 55°C ● Add 50 mL of Middlebrook OADC enrichment (BD 212240) ● Keep at 55℃ ● Pipette 20 mL agar solution/plate ● Store at 4°C until ready to use after coagulation

Results [Table 45] research group Treatment (compound/concentration, μg/ml) log 10 1 CAM 1 μg/ml >5.70 2 CFZ 1 μg/ml >5.70 8 I-1-3 1 μg/ml >5.70 4 CAM 1 μg/ml + CFZ 1 μg/ml >5.70 5 CAM 1 μg/ml + CFZ 1 μg/ml + I-1-3 1 μg/ml 4.90 6 Control (Day 0) 5.93 7 Control (Day 2) >5.70 The above results can be seen with reference to Figure 11, which shows the respective log10 values of CFU for each of the 7 study groups. It also exhibited an "upper limit" value of 5.70, which is basically a value at which the CFU is too high for it to be accurately measured. • Only group 5 showed bactericidal effect when the log10 CFU was 4.90.

Based on the above test results, the medicament of the present invention may be an applicable agent for treating and/or preventing symptoms and/or diseases induced by mycobacterial infection.

The efficacy as a drug can be checked by the following tests, etc.

Test Example 14: CYP Inhibition Test Using commercially available pooled human liver microsomes, the degree of inhibition of the compounds of the present invention on the production of each metabolite was assessed as marker responses for the following five major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A4): 7-ethoxyresorufin O-deethylation (7-ethoxyresorufin O-deethylation) (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (mephenytoin 4'-hydroxylation) (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation (CYP3A4).

The reaction conditions are as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenytoin (CYP2C19), 5 μmol /L Dextromethorphan (CYP2D6), 1 μmol/L Terfenadine (CYP3A4); Reaction time, 15 minutes; Reaction temperature, 37°C; Enzymes, pooled human liver microsomes 0.2 mg protein/ml; Compound of the present invention Concentration, 1.0, 5.0, 10, 20 μmol/L (four points).

Each of the five substrates, human liver microsomes, or 50 mmol/L Hepes buffer containing the compound of the invention was added to a 96-well plate with the composition as described above, and NADPH was added as a cofactor to trigger a metabolic reaction. After incubation at 37°C for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, the resorufin (CYP1A2 metabolite) in the supernatant was quantified by fluorescent multilabel counter or LC/MS/MS, and by LC/MS/MS p-hydroxytoluene Sulfabutamide (CYP2C9 metabolite), 4'hydroxymephenytoin (CYP2C19 metabolite), dexoxymorphan (CYP2D6 metabolite) and terfenadine metabolite (CYP3A4 metabolite) were quantified.

A sample obtained by adding only DMSO, which is a solvent for dissolving compounds other than the compound of the present invention, to the reaction mixture was used as a control (100%). Compared with the control, the remaining activity (%) was calculated at each concentration of the compound of the present invention, and the IC ₅₀ was calculated by inversion by the logistic model by using the concentration and the inhibition rate.

Test Example 15: CYP3A4 (MDZ) MBI Test The CYP3A4 (MDZ) MBI test is a test to investigate the mechanism-based inhibition (MBI) potential of the compounds of the invention for CYP3A4 inhibition by enhancing the inhibition caused by the metabolic response of the compounds of the invention. CYP3A4 inhibition was assessed using pooled human liver microsomes by 1-hydroxylation of midazolam (MDZ) as a marker reaction.

The reaction conditions are as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; 0.5 mg/mL, 0.05 mg/mL during reaction (10-fold dilution); concentration of the compound of the present invention, 1, 5, 10, 20 μmol/L or 0.83, 5, 10 and 20 μmol/L (four points).

A solution of pooled human liver microsomes and the compound of the present invention in K-Pi buffer (pH 7.4) was added to a 96-well plate as a pre-reaction solution with a pre-reaction composition. A portion of the pre-reaction solution was transferred to another 96-well plate and diluted 1/10 by K-Pi buffer containing substrate. NADPH was added as a cofactor to initiate the reaction as a marker reaction (pre-incubation 0 min). After the reaction of the marker for a predetermined time, a solution of methanol/acetonitrile=1/1 (v/v) was added to stop the reaction. Additionally, NADPH was added to the remaining pre-reaction solution to initiate the pre-reaction (30 min pre-incubation). After a predetermined time of pre-reaction, a portion was transferred to another 96-well plate, and a 1/10 dilution was performed by K-Pi buffer containing substrate to initiate a reaction as a labeling reaction. After the reaction of the marker for a predetermined time, a solution of methanol/acetonitrile=1/1 (v/v) was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, 1-hydroxymidazolam in the supernatant was quantified by LC/MS/MS.

A sample obtained by adding only DMSO, which is a solvent for dissolving compounds other than the compound of the present invention, to the reaction mixture was used as a control (100%). Compared with the control, the remaining activity (%) was calculated at each concentration of the compound of the present invention, and the IC value was calculated by back-calculating by the logistic model by using the concentration and the inhibition rate. The shifted IC value was calculated as "IC of pre-incubation for 0 min/IC of pre-incubation for 30 min". This was defined as positive when the shift IC was 1.5 or greater. Negative was defined when the shift IC was 1.0 or less.

Test Example 16: BA Test Experimental Materials and Methods for Evaluation of Oral Absorption (1) Animals: use rats (2) Breeding conditions: the mice or rats were allowed to freely obtain solid food and sterilized tap water. (3) Dosage and grouping: administered orally or intravenously at a predetermined dose; the grouping is as follows (the dose depends on the compound) Oral administration: 2 to 60 μmol/kg or 1 to 30 mg/kg (n=2 to 3) Intravenous administration: 1 to 30 μmol/kg or 0.5 to 10 mg/kg (n=2 to 3) (4) Preparation of administration solution: for oral administration, it is in the state of solution or suspension; for intravenous administration, it is in the state of dissolution (5) Administration method: For oral administration, use an oral probe to force administration into the stomach; for intravenous administration, use a syringe equipped with a needle to administer from the tail vein (6) Evaluation item: Blood is collected over time, and the plasma concentration of the drug is measured by LC/MS/MS (7) Statistical analysis: Regarding the transition of the plasma concentration of the compound of the present invention, the area under the plasma concentration-time curve (AUC) was calculated by the non-linear least squares program WinNonlin (Registered trademark), and according to the oral administration group and Bioavailability (BA) was calculated from the AUC of the intravenously administered group.

Test Example 17: Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. Inoculate 20 µL of frozen-stored Salmonella typhimurium ( Salmonella typhimurium ) (TA98 strain, TA100 strain) on 10 mL of liquid nutrient medium (2.5% Oxoid nutrient medium No. 2), and shake it at 37°C Incubate for 10 hours. Centrifuge 7.70 to 8.00 mL of TA98 medium (2000 x g, 10 min). Bacteria were suspended in Micro F buffer (K ₂ HPO ₄ : 3.5 g/L, KH ₂ PO ₄ : 1 g/L, (NH ₄ ) ₂ SO ₄ : 1 g/L, trisodium citrate dihydrate: 0.25 g/L and MgSO ₄ •7H ₂ 0: 0.1 g/L). The suspension was added to 120 mL exposure medium (Micro F buffer containing the following: biotin: 8 μg/mL, histidine: 0.2 μg/mL and glucose: 8 mg/mL). Mix 3.10 to 3.42 mL of TA100 medium strain with 120 to 130 mL of exposure medium. Mix 12 μL each of the compounds of the present invention in DMSO (multi-stage dilutions at a 2- to 3-fold ratio from the maximum dose of 50 mg/mL), DMSO as a negative control, and 50 μg/mL in assays without metabolic activation 4-nitroquinoline 1-oxide DMSO solution for TA98 strain and 0.25 μg/mL 2-(2-furyl)-3-(5-nitro-2-furyl)propene for TA100 strain Amide DMSO solution, 40 μg/mL 2-aminoanthracene DMSO solution for TA98 strain and 20 μg/mL 2-aminoanthracene DMSO solution for TA100 strain in the analysis of metabolic activation as a positive control, and 588 μL of test bacterial suspension (498 μL and 90 μL of S9 mix in case of metabolic activation assay) and this was incubated at 37° C. for 90 minutes with shaking. Mix 460 μL of the mixture with 2300 μL of indicator medium (Micro F buffer containing 8 μg/mL biotin, 0.2 μg/mL histidine, 8 mg/mL glucose, 37.5 μg/mL bromocresol purple) Mixed, 50 μL of each was dispensed into microplates 48 wells/dose, and this was incubated at 37°C for 3 days. The number of yellow wells out of 48 wells was counted per dose as wells containing bacteria that acquired the ability to grow through a point mutation in the amino acid (histidine) synthase gene changed from purple to yellow due to the pH change , and compared it with the negative control group. (-) and (+) mean mutagenicity negative and positive, respectively.

Test Example 18: hERG Test For the purpose of assessing the risk of ECG QT interval prolongation of the compounds of the present invention, the effect of the compounds of the present invention on ventricular repolarization was studied using CHO cells expressing the human ether-a-go-go-related gene (hERG) channel The influence of the delayed rectifier K+ current (I _Kr ), which plays an important role in the process of magnification. After keeping cells at a membrane potential of -80 mV and obtaining a leak potential of -50 mV by the whole-cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A/S), recordings were made from +20 mV for 2 I _Kr induced by a depolarizing pulse of -50 mV for 2 s and further stimulated by a repolarizing pulse of -50 mV for 2 s. Extracellular solution adjusted to contain 0.1% dimethyloxide (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl ₂ : 2 mmol/L, MgCl ₂ : 1 mmol/L, glucose: 10 mmol/L L, HEPES (4-(2-hydroxyethyl)-1-piperethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperethanesulfonic acid): 10 mmol/L, pH =7.4) Used as a culture medium. The extracellular solution in which the medium and the compound of the present invention had been dissolved at each target concentration was applied to the cells at room temperature for 7 minutes or more. Based on the recorded I _Kr , the absolute value of the tail peak current was measured based on the current value at resting membrane potential using analysis software (QPatch analysis software; Sophion Bioscience A/S). In addition, the tail current after application of the compound of the present invention relative to the tail current after application of the medium was calculated as % inhibition to assess the effect of the compound of the present invention on I _Kr .

Test Example 19: Solubility Test The solubility of the compounds of the present invention was determined with the addition of 1% DMSO. Prepare 10 mmol/L compound solution with DMSO. 2 μL of the compound solution of the present invention was added to 198 μL of JP-1 fluid or JP-2 fluid, respectively. The mixture was shaken at room temperature for 1 hour and the mixture was vacuum filtered. Dilute the filtrate 10 times or 100 times with methanol/water=1/1 (v/v) or acetonitrile/methanol/water=1/1/2 (v/v/v), and use LC/MS or solid phase Extraction (SPE)/MS measures the concentration of compounds in the filtrate by an absolute calibration method.

The composition of JP-1 fluid is as follows. Water was added to 2.0 g sodium chloride and 7.0 mL hydrochloric acid to make 1000 mL. The composition of JP-2 fluid is as follows. 1 volume of water was added to 1 volume of solution, wherein 3.40 g of monobasic potassium phosphate and 3.55 g of anhydrous disodium hydrogen phosphate were dissolved in water to make 1000 mL.

Test Example 20: Powder Solubility Test An appropriate amount of a compound of the invention is placed in a suitable container. Add 200 μL of JP-1 fluid (add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL), 200 μL of JP-2 fluid (add 1 volume of water to 1 volume of solution with 3.40 g monobasic potassium phosphate and 3.55 g anhydrous disodium hydrogen phosphate dissolved in water to make up to 1000 mL) or 20 mmol/L sodium taurocholate (TCA)/JP-2 fluid (add JP-2 fluid to 1.08 g TCA to reach 100 mL) to each container independently. When the total amount is dissolved after adding the test reagent, the compound of the present invention is appropriately added. After sealing and shaking for 1 hour at 37°C, the solution was filtered and 100 μL methanol was added to 100 μL of each filtrate to dilute two-fold. Dilution rates vary as needed. After checking for the absence of bubbling and precipitation, the container was sealed and shaken. Compounds of the invention were measured by the absolute calibration curve method using HPLC.

Test Example 21: P-gp Substrate Test The compound of the present invention was added to one side of Transwell (registered trademark, CORNING) in which cells or blasts expressing human MDR1 had been cultured in a monolayer. The cellular response is allowed to last for a constant time. Calculate the membrane permeability coefficient from the top side to the bottom side (A→B) and from the bottom side to the top side (B→A) of MDR1-expressing cells or blast cells, and calculate the efflux ratio of MDR1-expressing cells and blast cells (ER; the ratio of the membrane permeability coefficient of B→A and A→B) value. The efflux ratio (ER) values of MDR1 expressing cells and blast cells were compared to confirm whether the compounds of the invention would be substrates of P-gp.

Formulation example The formulation examples below are illustrative only and are not intended to limit the scope of the invention.

Formulation Example 1: Lozenges The compound used in the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to obtain granules of suitable size. Subsequently, calcium stearate is added to the granules, and the mixture is compressed and molded to obtain lozenges.

Formulation Example 2: Capsules The compound used in the present invention, lactose and calcium stearate are uniformly mixed to obtain a powder drug in the form of powder or fine granules. Powdered medicine is filled into capsule containers to obtain capsules.

Formulation Example 3: Granules The compounds used in the present invention, lactose and calcium stearate were uniformly mixed and the mixture was compressed and molded. Subsequently, it is crushed, granulated and sieved to obtain granules of suitable size.

Formulation Example 4: Orally Disintegrating Lozenges The compound used in the present invention is mixed with crystalline cellulose, granulated and tabletted to obtain orally disintegrating tablets.

Formulation Example 5: Dry Syrup The compound used in the present invention is mixed with lactose, crushed, granulated and sieved to obtain a dry syrup of suitable size.

Formulation Example 6: Injection Compounds used in the present invention are mixed with phosphate buffer to obtain injection solutions.

Formulation Example 7: Infusion Solution Compounds used in the present invention are mixed with phosphate buffer to obtain injection solutions.

Formulation Example 8: Inhalants The compound used in the present invention is mixed with lactose and finely crushed to give an inhalant.

Formulation Example 9: Ointment A compound used in the present invention is mixed with paraffin oil to give an ointment.

Formulation Example 10: Patch The compound used in the present invention is mixed with a base such as adhesive plaster or the like to obtain a patch. [industrial applicability]

The medicament of the present invention may be a drug suitable for treating and/or preventing symptoms and/or diseases induced by mycobacterial infection.

[Fig. 1] Fig. 1 shows the mean log10 values of CFU in each lung of the 15 study groups after the end of treatment, as described below (13 study groups included clarithromycin (CAM), clofazimine (CFZ) , cytochrome bc1 inhibitors and various combinations of treatment regimens, and the two study groups were the control group). The X-axis indicates each study group. The Y-axis indicates the mean log10 value of CFU. [Fig. 2] Fig. 2 shows the mean log10 values of CFU in each lung of the 6 study groups after the end of treatment, as described below (4 study groups included clarithromycin (CAM), CFZ, cytochrome bc1 inhibitor and various combinations of treatment plans, and the two research groups were the control group). The X-axis indicates each study group. The Y-axis indicates the mean log10 value of CFU. [Fig. 3] Fig. 3 shows the mean log10 values of CFU in each lung of the 15 study groups after the end of treatment, as described below (13 study groups included clarithromycin (CAM), CFZ, cytochrome bc1 inhibitor and various combinations of treatment plans, and the two research groups were the control group). The X-axis indicates each study group. The Y-axis indicates the mean log10 value of CFU. [Fig. 4] Fig. 4 shows the mean log10 values of CFU in each lung of the 6 study groups after the end of treatment, as described below (4 study groups included azithromycin (AZM), rifampicin (RFP) ), ethambutol (ETB), CFZ, cytochrome bc1 inhibitors and various combinations, and the two study groups were the control group). The X-axis indicates each study group. The Y-axis indicates the mean log10 value of CFU. [FIG. 5] FIG. 5 shows the log10 values of CFU for each of the 12 study groups, as described below (10 study groups contained conditions containing clarithromycin (CAM) or cytochrome bcl inhibitor, and 2 study group as the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU. [FIG. 6] FIG. 6 shows the log10 values of CFU for each of the 30 study groups, as described below (28 study groups included CAM containing clarithromycin (CAM) or a combination of CAM and cytochrome bcl inhibitor conditions, and the two research groups were the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU. [FIG. 7] FIG. 7 shows the log10 values of CFU for each of the 11 study groups, as described below (9 study groups included CAM containing clarithromycin (CAM) or a combination of CAM and cytochrome bcl inhibitor conditions, and the two research groups were the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU. [FIG. 8] FIG. 8 shows the log10 values of CFU for each of the 26 study groups, as described below (the 24 study groups included clarithromycin (CAM), I-1-3, or CAM with I- 1-3 combined conditions, and the 2 research groups are the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU. [FIG. 9] FIG. 9 shows the log10 values of CFU for each of the 6 study groups, as described below (4 study groups included clarithromycin (CAM), I-1-3, CAM and chlorine method Conditions of the combination of Qi Ming (CFZ) or the combination of CAM, CFZ and I-1-3, and the two research groups are the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU. [Fig. 10] Fig. 10 shows the mean log10 values of CFU in each lung of the 6 study groups after the end of treatment, as described below (6 study groups included clarithromycin (CAM), rifamycin (RFP) , ethambutol (ETB), CFZ, cytochrome bc1 inhibitors and various combinations, and the two study groups were the control group). The X-axis indicates each study group. The Y-axis indicates the mean log10 value of CFU for each lung. [FIG. 11] FIG. 11 shows the log10 values of CFU for each of the 7 study groups, as described below (5 study groups included clarithromycin (CAM), clofazimine (CFZ), I- 1-3, the conditions of the combination of CAM and CFZ or the combination of CAM, CFZ and I-1-3, and the two research groups are the control group). The X-axis indicates each study group. The Y-axis indicates the log10 value of CFU.

Claims (24)

A kind of medicine, it is characterized in that, (A) is represented by the compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; Combined use of (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof; Scientifically acceptable salt. The medicine according to claim 1, wherein R ¹ and R ⁴ are hydrogen atoms. The medicine according to claim 1, wherein R ² is a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group. The medicine according to claim 1, wherein R ³ is a hydrogen atom or a halogen. The drug according to claim 1, wherein R ⁵ is a substituted or unsubstituted alkyl group. The medicine according to claim 1, wherein R ⁶ , R ⁸ and R ⁹ are hydrogen atoms, and R ⁷ is halogen. The medicine as claimed in item 1, wherein X is N. The medicine as claimed in item 1, wherein Y is N. The medicine as claimed in item 1, wherein m is 1. The drug according to claim 9, wherein R ¹⁰ is a substituted or unsubstituted alkyl group. The drug according to claim 1, wherein R ¹¹ is a substituted or unsubstituted alkoxy group. The medicine as claimed in item 1, wherein n is 0. The medicine as claimed in item 1, wherein (A) is a compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof. The medicine according to claim 1, wherein (B) is clarithromycin or a pharmaceutically acceptable salt thereof. The drug as claimed in item 1, wherein (A), (B) and (C) are administered simultaneously, sequentially or at intervals. The medicine according to claim 1, wherein the medicine is a combination medicine. The medicament according to claim 1, wherein the medicament is used for treating or preventing mycobacterial infection. A kind of antibacterial effect of enhancing (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine or its pharmaceutically acceptable salt A method of activity comprising administering (B) clarithromycin or a pharmaceutically acceptable salt thereof or azithromycin or a pharmaceutically acceptable salt thereof and (C) clofazimine or a pharmaceutically acceptable salt thereof and the compound represented by formula (I) as claimed in Claim 1 or a pharmaceutically acceptable salt thereof. A method for enhancing the antibacterial activity of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising administering the compound represented by formula (I) or its pharmaceutically acceptable salt as claimed in claim 1 Pharmaceutically acceptable salt and (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine or its pharmaceutically acceptable salt Salt. The method as claimed in item 18, wherein the (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine or its pharmaceutically acceptable salt The acceptable salt is administered simultaneously, sequentially or at intervals with the therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1. The method of claim 19, wherein the compound represented by formula (I) or its pharmaceutically acceptable salt as claimed in claim 1 is combined with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt or azithromycin or a pharmaceutically acceptable salt thereof and/or (C) clofazimine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or at intervals. A method of treating mycobacterial infection, comprising administering a therapeutically effective amount of a combination of the following to an individual in need of treatment of mycobacterial infection: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof. The method of claim 22, wherein (A) is represented by formula (I) or a pharmaceutically acceptable salt thereof, (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof The above acceptable salt and (C) clofazimine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or at intervals. A pharmaceutical composition or kit comprising: (A) a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R ⁵ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, provided that R ^6. R ⁷ , R ⁸ and R ⁹ are not hydrogen atoms at the same time; X is CH or N; Y is CH or N; R ¹⁰ is each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R ¹¹ is halogen, hydroxyl, cyano, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, or pentafluorothio; R ¹² are each independently halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; (B) clarithromycin or a pharmaceutically acceptable salt thereof, or azithromycin or a pharmaceutically acceptable salt thereof; and (C) clofazimine or a pharmaceutically acceptable salt thereof.

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